" Nucleolus in Human Beasons: Ribosome Biogenesis " , " Nucleolar Survey " и " Terrapeutic Opportunities " .

1. Introduction

The human nucleolus is a dynamic subnuclear compartment that integrates ribosome biogenesis (RiBi) with pathways governing cellular growth, stress responses, and homeostasis. While traditionally viewed solely as a site of ribosome production, the nucleolus is now recognised as a multifunctional organelle whose structure and activity are tightly coupled to cellular state. In addition to its role in RiBi, the nucleolus integrates transcriptional networks and the Nucleolar Surveillance Pathway, a stress-sensing mechanism activated by perturbations to nucleolar integrity that elicits responses ranging from cell cycle arrest and apoptosis to cellular preservation, thereby shaping genome function and cell fate.

Disruption of nucleolar function has profound biological consequences. Aberrant nucleolar function that drives dysregulated ribosomal DNA transcription supports proliferative demands in cancer, whereas impaired nucleolar output resulting in reduced ribosome production and defective nucleolar surveillance underlies a clinically heterogeneous group of disorders termed ribosomopathies. In these settings, nucleolar dysfunction is not simply a downstream consequence of disease but an active driver of pathology, positioning the nucleolus as a central yet incompletely understood regulator of cellular physiology and human disease. In this review, we synthesise current understanding of nucleolar function and its disruption in disease, highlighting therapeutic vulnerabilities that arise and emerging strategies to exploit them, including small-molecule inhibitors and gene-based approaches.

2. The Nucleolus

The human nucleolus is a dynamic, membrane-less subnuclear organelle that plays an essential role in RiBi and functions as a central hub coordinating cellular growth and stress signalling pathways. Nucleoli assemble around actively transcribed 47S ribosomal RNA (rRNA) genes, known as ribosomal DNA (rDNA), which are clustered in nucleolar organiser regions (NORs) on the short arms of the five acrocentric chromosomes in humans (13, 14, 15, 21, and 22) [ 1 , 2 ]. The nucleolus exhibits a highly organised structure comprising three immiscible concentric sub-compartments: the innermost fibrillar centre (FC), the surrounding dense fibrillar component (DFC), and the outer granular component (GC), within which multiple FC-DFC modules are embedded ( Figure 1 ) [ 3 , 4 ]. The GC is encircled by perinucleolar chromatin (PC), a ring of condensed, transcriptionally inactive chromatin enriched in developmental and sensory perception genes that may also extend into the nucleolar interior [ 3 , 5 , 6 ]. This multilayered organisation arises through reversible liquid–liquid phase separation (LLPS), driven in part by the nucleolar proteins fibrillarin (FBL) and nucleophosmin (NPM1) [ 3 , 4 , 7 ]. Collectively, this organisation reflects a functional architecture in which spatial compartmentalisation is tightly coupled to sequential steps in rDNA transcription, rRNA processing, and ribosomal subunit assembly ( Figure 1 ).

While the nucleolus is implicated in a broad range of cellular processes, this review outlines its canonical role in RiBi and stress signalling, both of which are implicated in the pathophysiology of diverse diseases.

3. The Nucleolus Coordinates Ribosome Biogenesis

3.1. Ribosome Biogenesis

3.1.1. Transcription of rDNA

RiBi in mammalian cells ( Figure 2 ) is spatially organised within the nucleolus, whose three sub-compartments coordinate successive steps of the process ( Figure 1 ) [ 3 , 4 ]. It begins with transcription of 47S precursor rRNA (pre-rRNA) from rDNA repeats by RNA Polymerase I (Pol I) at the FC-DFC interface, where active Pol I complexes are enriched [ 3 , 4 ]. In contrast, the FC contains unengaged Pol I factors, while the GC contains inactive rDNA repeats [ 3 , 4 ]. These rDNA repeats, present at ~200–600 copies in the human genome, account for ~60% of total cellular transcription [ 8 , 9 , 10 , 11 ]. However, only a portion are actively transcribed at any time, with activity governed by upstream signalling and epigenetic state [ 12 , 13 ].

Structurally, human rDNA repeats are predominantly arranged in head-to-tail tandem arrays, with about one third inverted or palindromic [ 14 ]. Each repeat comprises a transcribed region followed by an intergenic spacer (IGS) with 5′ and 3′ terminator elements [ 10 , 12 ]. The transcribed region encodes the 47S pre-rRNA, which gives rise to 18S, 5.8S, and 28S rRNAs separated by internal transcribed spacers (ITS1, ITS2) and flanked by external transcribed spacers (5′ ETS, 3′ ETS) [ 10 , 12 ]. The IGS contains regulatory elements including the rDNA promoter, comprising an upstream control element (UCE) and core region, and spacer promoters upstream of enhancers [ 10 , 12 ].

Pol I transcription is initiated by binding of upstream binding factor (UBF) and the selectivity factor 1 (SL1) complex, composed of TATA-binding protein (TBP) and five Pol I-specific TBP-associated factors (TAFs), to the rDNA promoter, where the preinitiation complex (PIC) assembles ( Figure 2 ) [ 15 ]. The PIC recruits Pol I via transcription initiation factor-IA (TIF-IA/RRN3), enabling stable Pol I-SL1 engagement and promoter escape [ 15 ].

3.1.2. Pol II and Pol III Transcription and Pre-rRNA Processing

5S rRNA is transcribed by RNA Polymerase III (Pol III) from tandem repeats on the distal end of chromosome 1 in the nucleoplasm [ 16 ]. RNA Polymerase II (Pol II) transcribes genes encoding the ~80 ribosomal proteins (RPs), over 200 RiBi assembly factors, and over 200 small nucleolar RNPs (snoRNPs) in the nucleoplasm [ 17 , 18 , 19 ]. Pol II has been proposed to facilitate rRNA expression by regulating Pol I-dependent intergenic noncoding RNAs in mouse nucleoli [ 20 ]; however, whether this mechanism is conserved in humans remains unclear, with corresponding transcripts not detected in our analysis of human RNAseq data (unpublished observations). RPs and assembly factors are translated in the cytoplasm, then imported into the nucleus via importins and karyopherins recognising nuclear localisation signal (NLS) motifs, with nucleolar entry facilitated by nucleolar localisation signals (NoLS) [ 21 , 22 , 23 ].

Following 47S pre-rRNA transcription, nascent transcripts are sorted from the FC-DFC interface to the DFC, which is enriched in pre-rRNA processing and modification factors [ 3 , 4 ]. Pre-rRNAs associate co-transcriptionally with RPs and snoRNPs, undergoing folding, chemical modification (primarily 2′-O-ribose methylation and pseudouridylation catalysed by C/D and H/ACA box snoRNPs), and sequential endo- and exonuclease cleavage at multiple spacer sites to generate processing intermediates and, ultimately, the mature 5.8S, 18S, and 28S rRNAs [ 17 , 24 , 25 ].

3.1.3. Ribosomal Subunit Assembly

Following rRNA processing, RiBi continues in the GC, which contains maturing ribosomal subunits and supports later stages of assembly [ 3 , 26 ]. Within the GC, RPs assemble stepwise with rRNAs to form pre-60S and pre-40S ribosomal subunits, with the latter maturing from a small subunit (SSU) processome [ 27 , 28 , 29 ]. In the nucleoplasm, 5S rRNA associates with RPL5 and RPL11 to form the trimeric 5S-ribonucleoprotein particle (5S-RNP), which assembles late onto maturing pre-60S subunits with the assistance of assembly factors, including regulator of ribosome synthesis 1 homolog (RRS1), brix domain-containing protein 1 homolog (BXDC1), and HEAT-repeat containing 3 (HEATR3), forming the central protuberance essential for ribosome function [ 30 , 31 , 32 , 33 ].

The pre-40S and pre-60S subunits are exported through the nuclear pore complex (NPC) and undergo final maturation in the cytoplasm to generate the mature 40S (small) and 60S (large) subunits, with some RPs assembling during both nuclear and cytoplasmic stages [ 29 , 34 , 35 ]. The mature 40S subunit contains ~33 RPs and 18S rRNA, and the 60S subunit comprises ~47 RPs along with 5S, 5.8S, and 28S rRNAs [ 36 ]. For translation initiation, the small subunit binds the 5′ end of mRNA and scans the 5′ untranslated region (UTR) until reaching the AUG start codon, where the 60S subunit joins to form the functional 80S ribosome [ 37 ]. During translation, the 40S subunit decodes codons via transfer RNA (tRNA) anticodons and the 60S subunit catalyses peptide bond formation via its peptidyl transferase centre, elongating the polypeptide chain [ 38 ]. As RiBi and translation are essential for cell growth and proliferation, yet highly energetically demanding processes, they are tightly regulated at multiple levels to match cellular metabolic state and proliferative demands, as discussed in the following sections.

3.2. Regulation of Ribosome Biogenesis

RiBi is the most energy-intensive cellular process and is therefore tightly regulated by cellular stress and nutrient availability, including amino acids, glucose, insulin, fatty acids, and growth factors, to balance energy expenditure with growth and proliferation [ 39 , 40 ]. These regulatory inputs are mediated through interconnected signalling pathways that couple environmental and cellular cues to nucleolar function. Multiple signalling networks, including PI3K/AKT/mTORC1, mitogen-activated protein kinase (MAPK), MYC, and CDK-cyclin complexes, integrate extracellular and intracellular signals to control RiBi at both transcriptional and translational levels, including through epigenetic regulation of rDNA activity [ 40 , 41 ]. These signalling pathways are summarised in Figure 3 and briefly discussed below.

3.2.1. The PI3K/AKT/mTORC1 Pathway

The PI3K/AKT/mTORC1 pathway is activated by growth factor receptor tyrosine kinases (RTKs), which stimulate class 1A phosphoinositide 3-kinases (PI3Ks) to convert phosphatidylinositol 4,5-bisphosphate (PIP 2 ) to phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), a process antagonised by phosphatase and tensin homolog (PTEN) [ 42 , 43 ]. PIP 3 recruits AKT to the plasma membrane, where it is activated by phosphorylation at Thr308 by phosphoinositide-dependent protein kinase 1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) [ 44 , 45 ]. Activated AKT phosphorylates tuberous sclerosis protein 2 (TSC2), leading to activation of RheB, and phosphorylates proline-rich Akt substrate of 40kDa (PRAS40), relieving mTORC1 inhibition, thereby activating mTORC1 [ 46 , 47 ]. Activated mTORC1 subsequently phosphorylates ribosomal protein S6 kinase 1 (S6K1), which phosphorylates ribosomal protein S6 (RPS6), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) to promote RiBi, protein synthesis, and cell growth [ 48 , 49 , 50 ]. Through these effectors, the PI3K/AKT/mTORC1 pathway links growth factor signalling to ribosome production and translational output, ensuring that cellular protein synthesis capacity is matched to nutrient availability and growth demands.

3.2.2. The MAPK Pathway

MAPKs convert extracellular signals into intracellular responses, with extracellular signal-regulated kinase 1/2 (ERK1/2) being among the best characterised [ 51 ]. ERK1/2 is activated by RTKs, which recruit growth factor receptor-bound protein 2 (Grb2) and Son of Sevenless (SOS) to activate Ras [ 52 ]. Ras then activates Raf, which phosphorylates MEK1/2, leading to ERK1/2 activation [ 51 ]. Activated ERK1/2 translocates from the cytoplasm to the nucleus, where it phosphorylates UBF and RRN3 to promote rRNA synthesis, and phosphorylates ribosomal S6 kinase 1 (RSK1), which activates eukaryotic translation initiation factor 4B (eIF4B) to promote translation initiation [ 53 , 54 , 55 ]. This pathway therefore directly links mitogenic signalling to activation of Pol I transcription and RiBi. While the canonical ERK1/2, p38, and JNK pathways are well characterised, emerging evidence suggests that atypical MAPKs, including ERK3, ERK4, ERK7, ERK8, and Nemo-like kinase (NLK), also contribute to the regulation of cell growth and proliferation, with potential implications in cancer progression and immune signalling, highlighting additional layers of complexity within MAPK signalling networks [ 56 , 57 , 58 ].

3.2.3. MYC Regulation

The MYC proto-oncogene family, comprising MYC (c-Myc), MYCN (N-Myc), and MYCL (L-Myc), encodes transcription factors that control key cellular processes, including growth, differentiation, proliferation, cell cycle, DNA replication and repair, metabolism, and RiBi [ 59 , 60 , 61 , 62 ]. c-Myc is commonly hyperactivated in cancer, driving uncontrolled growth in part through increased ribosome production [ 63 , 64 ]. c-Myc promotes RiBi by coordinating transcription by all three RNA polymerases [ 65 ]. c-Myc enhances Pol I-mediated rRNA transcription by dimerising with MYC -associated factor X (MAX) to bind rDNA promoters, recruiting transformation/transcription domain-associated protein (TRRAP) and stimulating histone H3 and H4 acetylation to promote an open chromatin state [ 66 , 67 , 68 ]. c-Myc also complexes with transcription factor IIIB (TFIIIB) independently of MAX, recruiting lysine acetyltransferase 2A (KAT2A) and TRRAP to promote histone H3 acetylation, enhancing Pol III-mediated 5S rRNA and tRNA transcription [ 68 , 69 ]. For Pol II, c-Myc interacts with cyclin-dependent kinase 9 (CDK9) and recruits transcription elongation factor SPT5, promoting transcription of RP and RiBi factor genes [ 70 , 71 ]. In particular, c-Myc drives transcriptional upregulation of multiple core components of the Pol I transcriptional machinery, a level of coordinated regulation that is not observed for Pol II- or Pol III-associated components [ 65 ]. Through this integrated control of Pol I, II, and III, c-Myc functions as a central and uniquely positioned regulator of RiBi, coordinating both rDNA transcription and the biosynthetic capacity required to sustain ribosome production, particularly in proliferative and oncogenic contexts.

3.2.4. CDK-Cyclin-Dependent Regulation

CDK-cyclin complexes coordinate RiBi with cell cycle progression by phosphorylating key transcription and processing factors [ 41 ]. During G1, CDK2-cyclin E phosphorylates RRN3 at Ser44, stimulating Pol I transcription [ 72 ]. UBF is phosphorylated at Ser484 by CDK4-cyclin D1 and CDK2-cyclin E during G1, and at Ser388 by CDK2-cyclin A and E during S/G2, strengthening its interaction with Pol I and promoting rRNA synthesis [ 73 , 74 , 75 ]. ERK signalling further enhances Pol I activity during G1 and S phase through activation of CDK4 and CDK6 [ 76 ]. Furthermore, CDK9-mediated phosphorylation of Treacle promotes Pol I recruitment to rDNA [ 77 ]. In contrast, RiBi is suppressed during mitosis through CDK1-dependent phosphorylation of nucleolar proteins [ 41 , 78 , 79 ]. During mitosis, phosphorylation of UBF and CDK1-cyclin B-mediated phosphorylation of the SL1 subunit TAF1-110 at Thr852 inhibit rDNA transcription [ 80 , 81 , 82 ]. Several pre-rRNA processing factors, including NPM1, MPP10, and MPP6, are also phosphorylated during mitosis, although the functional consequences of these modifications remain unclear [ 41 , 83 , 84 , 85 ]. Upon mitotic exit, dephosphorylation by PP1 and PP2A restores nucleolar protein activity and reinitiates RiBi [ 79 ].

3.2.5. Epigenetic Regulation of rDNA Transcription

Although rDNA repeats are the most highly transcribed regions of the mammalian genome, a portion remain transcriptionally silenced, governed predominantly by epigenetic mechanisms that respond to energy status [ 12 , 13 , 86 ]. Active rDNA adopts a euchromatic, hypomethylated state enriched in active histone modifications upstream of enhancer regions, including the H2A.Z variant, H3 and H4 acetylation, and H3K4 methylation, whereas silent rDNA exhibits CpG hypermethylation alongside repressive modifications in the promoter, such as H4K16 and H4K20 deacetylation, H3K9 methylation, and H3K27me3 [ 12 , 13 , 87 , 88 ]. The switch between active and silent is driven primarily by three rDNA-silencing complexes. The nucleolar remodelling complex (NoRC), comprising SNF2h and TIP5, recruits the noncoding promoter-associated RNA (pRNA), DNMTs, and histone-modifying enzymes to block assembly of the PIC at the rDNA promoter [ 89 ]. The energy-dependent nucleolar silencing complex (eNoSC), composed of SUV39H1, NML, and SIRT1, silences rDNA in response to glucose starvation, protecting cells from energy-deprivation-induced apoptosis [ 90 , 91 ]. The nucleosome remodelling and deacetylation complex (NuRD), containing HDAC1/2, CHD3/4, GATAD2A/2B, RBBP7/4, MTA1/2/3, and MBD2/3, is activated by reduced cell growth and establishes a “poised” chromatin state that maintains silencing [ 92 ]. These complexes act within a broader, interdependent network of histone- and DNA-modifying proteins that reinforce rDNA transcriptional repression [ 12 , 13 , 86 ]. Beyond transcriptional regulation, rDNA silencing preserves genome stability by limiting aberrant recombination between sister chromatids [ 13 , 93 ]. Accordingly, its disruption is implicated in genome instability and, consequently, ageing and disease, including cancer and developmental, haematopoietic, autoimmune, and neurological disorders [ 94 ].

4. The Nucleolar Proteome

4.1. Early Mass Spectrometry Mapping of the Nucleolar Proteome

4.1.1. Redefining the Nucleolus: Multifunctionality Beyond Ribosome Biogenesis

For much of the twentieth century, the nucleolus was viewed primarily as the site of RiBi. This view was challenged in 1998 when Thoru Pederson proposed the concept of a “plurifunctional nucleolus”, suggesting that the nucleolus supports processes beyond ribosome production [ 95 ]. This shift reframed the nucleolus as a dynamic regulatory hub rather than a structure dedicated solely to ribosome synthesis. The first efforts to define the nucleolar proteome began in 2002 with two independent mass spectrometry (MS)-based proteomic analyses of purified human nucleoli from HeLa cells, published by Andersen et al. and Scherl et al. [ 96 , 97 ]. These studies identified ~350 nucleolar-associated proteins and provided the first systematic molecular definition of nucleolar composition [ 96 , 97 ]. As expected, RPs and additional RiBi factors constituted a substantial fraction of the datasets, consistent with the canonical role of the nucleolus [ 96 , 97 ]. However, a large proportion of identified proteins were previously uncharacterised or not known to localise to the nucleolus, including factors involved in translation and mRNA metabolism [ 96 , 97 ]. Scherl et al. cautioned that the translation-associated proteins may have co-purified artefactually, or, alternatively, that these proteins may localise to nucleoli transiently or at low abundance [ 97 ]. Nonetheless, the proteomic analyses provided early molecular support for the plurifunctional model and indicated that nucleolar activity extends beyond RiBi. The studies also provided evidence that the nucleolus responds to transcriptional and metabolic perturbation [ 96 ], with further studies supporting the concept that nucleolar organisation is not solely dependent on active rDNA transcription [ 98 ].

4.1.2. Limitations of Early Proteomic Approaches

Despite their impact, these fractionation-based proteomic studies have important limitations. Several well-established nucleolar proteins, including SL1 subunits, Gemin4, SRP68, and TERT, were not detected [ 96 , 97 ]. Additionally, of the ~700 proteins reported across these studies [ 96 , 97 , 98 ], only ~266 had experimental Gene Ontology validation for nucleolar localisation at the time of publication [ 99 ]. These discrepancies likely reflect technical constraints of the approach. Proteins that associate transiently or weakly with the nucleolus may dissociate during purification, while low-abundance or structurally atypical proteins may fall below detection thresholds or evade identification [ 100 ]. Conversely, contaminants may co-purify, reflecting the membrane-less nature of the nucleolus [ 100 ]. Further limitations arise from the use of a single cancer cell line, asynchronous cells, and a narrow range of cellular perturbations, which are unlikely to capture the full extent of context-dependent proteomic variation and cell cycle-specific dynamics. This is particularly important given evidence that nucleolar function is dysregulated in cancer ( Section 6.1 ) and closely linked to cell cycle control [ 101 ]. To address these limitations, subsequent MS-based studies expanded the scope to additional cell types and physiological contexts, identifying 872 nucleolar proteins in Jurkat T cells [ 102 ], 504 nucleolar proteins in developing rat cerebral cortex [ 103 ], many of which were associated with human neurodevelopmental disorders, and >4500 proteins in human nucleoli from diverse cell types under various conditions [ 104 ]. Together, these studies establish the nucleolus as a highly dynamic and context-dependent proteomic environment, reinforcing its role as a central integrator of cellular state.

4.2. The Human Protein Atlas as a Resource for the Nucleolar Proteome

More recently, insights into the nucleolar proteome have emerged from the Human Protein Atlas (HPA), which provides imaging-based protein subcellular localisation across 64 cell lines expressing ~98% of human protein-coding genes, providing broad proteome coverage [ 105 ]. Using HPA data, Stenström et al. in 2020 performed the first spatiotemporal mapping of the human nucleolar proteome across sub-compartments and cell cycle stages, identifying 1318 nucleolar proteins, of which 1031 localised to the whole nucleolus, 287 to the FC/DFC, and 157 to a distinct nucleolar rim [ 5 ]. Based on its distinct proteomic composition, this rim was proposed to represent a fourth nucleolar sub-compartment [ 5 ]. Over 87% of nucleolar proteins also localised to other cellular compartments, most commonly the nucleoplasm, cytosol, and mitochondria, indicating functions beyond RiBi [ 5 ]. Compared with datasets from Anderson et al. and Scherl et al., 550 proteins were not observed in the HPA dataset, while 1009 proteins were uniquely identified, including 292 not expressed in HeLa cells, highlighting the complementarity and cell-type dependence of these datasets [ 5 ].

Stenström et al. further characterised nucleolar proteome dynamics throughout the cell cycle with a single-cell imaging approach, an aspect not resolved by bulk MS approaches [ 5 ]. They identified 65 nucleolar proteins that re-localised during cell division to the chromosomal periphery, an RNA-protein sheath covering the outer surface of mitotic chromosomes, including 36 not previously reported at mitotic chromosomes, and 19 recruited late in mitosis, suggesting potential roles in nucleolar reassembly [ 5 ]. Proteins that relocated during mitosis were enriched in intrinsically disordered regions, consistent with roles in phase separation and condensate dynamics [ 5 ].

4.3. Emerging Strategies for Defining the Nucleolar Proteome

Immunofluorescence (IF)-based approaches offer several key advantages over MS-based approaches, including detection of low-abundance proteins, single-cell resolution, visualisation across the cell cycle, and characterisation of multi-compartment localisation, which is particularly important given the dynamic exchange of nucleolar components with the nucleoplasm [ 3 ]. However, the HPA dataset is limited by potential false positives from non-specific antibodies, incomplete localisation validation by knockdown or independent antibodies, fixation or staining artefacts, and computational classification of sub-compartments rather than marker-based experimental validation. Accordingly, imaging- and MS-based approaches are complementary for defining nucleolar proteome organisation and dynamics.

Beyond defining spatiotemporal information with imaging-based approaches, functional understanding of the nucleolus also requires mapping protein–protein interactions, as many nucleolar processes, including biochemical activity, biomolecular sequestration, and condensate formation, are mediated by dynamic interaction networks [ 3 ]. However, conventional nucleoli isolation is poorly suited to capturing transient or weakly associated nucleolar components, while also being labour-intensive and prone to sample degradation [ 100 ]. To overcome these limitations, proximity-labelling technologies have recently emerged to enable identification of nucleolar protein interaction networks, providing new insights into nucleolar biology.

Emerging technologies include DenseMAP, which resolved a GC-specific proteome and revealed insights into nucleolar protein quality control and stress responses [ 106 ]; light-induced targeting of endogenous condensates (LiTEC) combined with proximity-based biotinylation (BioID) to profile condensate protein interactomes [ 107 ]; ChIP-MS targeting RPA194 to identify rDNA-associated proteins in breast cancer [ 108 ]; and nucleolar beacon (NoB), which enabled analysis of nucleolar interactions in living cells without fractionation-based purification [ 109 ]. Collectively, these approaches provide powerful platforms for defining nucleolar interaction networks with temporal and contextual resolution.

Despite substantial progress, a single, definitive nucleolar proteome has yet to be defined. Instead, the nucleolus comprises overlapping, context-dependent proteomes influenced by cell type, developmental stage, physiological state, and stress conditions. Accordingly, integrating proximity-labelling, imaging, and MS-based approaches will be required to define how nucleolar composition is specified and remodelled across biological contexts.

4.4. Expanding Nucleolar Functions Beyond Ribosome Biogenesis

While many nucleolar proteins identified in proteomic studies remain functionally uncharacterised, leaving nucleolar functions incompletely understood, these datasets have nonetheless redefined the nucleolus from a structure dedicated to RiBi to a multifunctional regulatory hub. It is now implicated in diverse cellular processes, including responses to viral and bacterial infection [ 110 , 111 ], cell cycle regulation [ 112 , 113 ], assembly of non-ribosomal ribonucleoprotein (RNP) complexes [ 114 ], small interfering RNA (siRNA) regulation [ 115 ], non-ribosomal RNA transcription [ 116 ], telomere maintenance [ 117 , 118 ], the nucleolar DNA damage response (n-DDR) for repair of damaged rDNA [ 119 , 120 , 121 , 122 ], and coordination of cellular stress signalling [ 11 , 32 , 123 ].

Within this broader functional landscape, this review places a focus on nucleolar stress signalling, reflecting its broad implications for cell fate and disease, while recognising that it represents one of several key functional outputs of the nucleolus.

5. The Nucleolar Surveillance Pathway

Concurrent with the first nucleolar proteomic studies, Rubbi and Milner established that the nucleolus functions as a cellular stress sensor, monitoring disruptions in RiBi and directing cell fate decisions [ 123 ]. They provided the first evidence that inhibition of Pol I transcription activates p53 independently of DNA damage, leading to p53-dependent cell cycle arrest [ 123 ].

Further studies have shown that this stress sensor mechanism, termed the “Nucleolar Surveillance Pathway” (NSP; or Nucleolar Stress Response), is initiated by stressors that disrupt nucleolar integrity. These include perturbations to rRNA transcription or processing, ribosome assembly or export, and rDNA damage (collectively referred to as ribosomal stress), as well as nutrient or serum starvation, cell contact inhibition, pH changes, ultraviolet radiation, viral infection, aberrant protein accumulation, impaired transcription or translation, hypoxia, reactive oxygen species (ROS) accumulation, non-ribosomal DNA damage, and oxidative, osmotic, thermal, oncogenic, or metabolic stress [ 11 , 32 , 119 , 123 , 124 , 125 , 126 ].

Several of these stressors, including nutrient starvation, oncogenic signalling, and metabolic stress, act primarily through the RiBi-regulatory pathways discussed in Section 3.2 . DNA damage and ROS accumulation, by contrast, act directly at the level of rDNA integrity, disrupting nucleolar organisation through distinct mechanisms. rDNA repeats are particularly susceptible to genomic insult due to their high copy number, repetitive structure, and high transcriptional activity [ 119 , 121 , 127 ]. DNA damage at rDNA loci can trigger the n-DDR [ 119 , 120 , 121 , 122 ], providing a route into the NSP distinct from DNA damage-independent activation. ROS accumulation similarly damages rDNA, activating the n-DDR and converging on this same route to p53 stabilisation [ 128 ].

In response to rDNA damage, the n-DDR transiently inhibits Pol I transcription and reorganises the nucleolus into nucleolar “caps” to facilitate repair [ 119 , 121 , 122 , 129 ]. Within the nucleolus, Treacle (TCOF1) is a central regulator of this repair process, recruiting the MRE11-RAD50-NBS1 (MRN) complex and TOPBP1 to damaged rDNA following APE1-mediated ataxia telangiectasia mutated (ATM)/ataxia telangiectasia and Rad3 related (ATR) activation [ 122 , 130 , 131 , 132 , 133 , 134 , 135 ]. This is exemplified in the ribosomopathy Treacher Collins Syndrome (TCS), in which TCOF1 dysfunction is linked to elevated DNA damage in model systems [ 136 , 137 , 138 , 139 ].

Given the vulnerability of rDNA loci to DNA damage, several global DDR factors also localise to the nucleolus and contribute to n-DDR signalling, with additional effectors continuing to be identified [ 120 ]. For example, poly(ADP-ribose) polymerase 1 (PARP1) associates with the NoRC subunit TIP5 to silence rDNA transcription and interacts with the RecQ helicases Bloom syndrome protein (BLM) and Werner syndrome helicase (WRN) [ 140 , 141 , 142 ]. These helicases support Pol I transcription while also resolving topological and replication-associated stress at rDNA loci, indicative of a dual functional role [ 143 , 144 , 145 ]. As n-DDR defects promote rDNA instability and cancer progression [ 120 ], further elucidating their mechanisms and crosstalk with global DNA repair may reveal how nucleolar surveillance coordinates DNA damage responses, while also identifying potential therapeutic targets.

Depending on the duration and severity of the insult, the NSP can trigger responses ranging from apoptosis to cellular preservation, thereby playing a critical role in maintaining genomic integrity [ 11 , 125 ]. NSP activation primarily stabilises the transcription factor and tumour suppressor protein p53 ( TP53 ), termed the p53-dependent NSP, although p53-independent NSP responses have also been described, both of which are discussed in the following sections.

5.1. p53-Dependent Nucleolar Surveillance Pathways

5.1.1. The Ribosomal Protein-MDM2-p53 Axis

Activation of the NSP stabilises p53 primarily through a 5S-RNP-dependent mechanism ( Figure 4 ). Under exponential growth conditions, p53 levels are regulated by the E3 ubiquitin ligase mouse double minute 2 (MDM2), which poly-ubiquitinates p53, targeting it for 26S proteasomal degradation [ 30 , 32 , 146 , 147 , 148 , 149 ]. NSP activity disrupts RiBi, causing ribosomal components, particularly the 5S-RNP, to accumulate in a “free” nucleoplasmic pool [ 30 , 32 , 146 , 147 , 148 , 149 ]. The 5S-RNP binds the central acidic domain of MDM2, inhibiting its activity and preventing p53 ubiquitination and degradation, resulting in p53 accumulation [ 30 , 32 , 146 , 147 , 148 , 149 ]. Stabilised p53 then induces transcription of its downstream effectors, promoting cell cycle arrest, apoptosis, senescence, or autophagy depending on the cellular context [ 30 , 32 , 146 , 147 , 148 , 149 , 150 ].

In addition to the 5S-RNP, multiple RPs contribute to NSP signalling by binding and inhibiting MDM2 in a context-dependent manner [ 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 ]. Additionally, 5S rRNA can inhibit the MDM2 homolog MDMX (MDM4), which suppresses p53 activity and enhances MDM2 function despite lacking intrinsic E3 ubiquitin ligase activity [ 166 ]. Among the RPs, RPL5 and RPL11, as components of the 5S-RNP, are essential for p53 activation, whereas additional RPs likely provide functional redundancy and context-specific modulation of the pathway [ 30 , 32 , 146 , 147 , 148 , 149 ].

The pathway is further regulated by feedback loops. MDM2 is a p53 transcriptional target, ensuring that p53 stabilisation induces MDM2 expression and subsequent p53 downregulation [ 147 , 150 ]. Additionally, p53 suppresses transcription of several RPs, including RPS27L and RPS25, restricting the pool of MDM2-interacting RPs [ 151 , 155 , 167 ]. Several RPs, including RPS7, RPL6, RPL26, and RPS27-like (RPS27L), are also direct substrates for MDM2-mediated degradation, further limiting their capacity to sustain p53 activation [ 151 , 165 , 168 , 169 ]. Thus, RPs both regulate and are regulated by the MDM2-p53 axis.

5.1.2. Additional Pathways of p53 Stabilisation

While the RP-MDM2-p53 axis is the primary driver of p53 stabilisation, additional pathways also exist and contribute to this response (outlined below and summarised in Figure 5 ).

PICT-1: RPL11 promotes p53 stabilisation through tumour suppressor protein interacting with carboxyl terminus 1 (PICT-1), which stabilises PTEN and functions as a 60S subunit biogenesis factor [ 170 , 171 ]. Under exponential growth conditions, PICT-1 retains RPL5 and RPL11 within the nucleolus through direct interaction with the 5S-RNP [ 30 ]. Upon DNA damage-induced nucleolar stress, PICT-1 is degraded, enabling RPL11 translocation into the nucleoplasm to enhance p53 stabilisation and apoptosis [ 172 , 173 , 174 ]. PICT-1 can also directly stabilise p53 under ribosomal stress, highlighting its dual role in coordinating RiBi and stress signalling [ 175 ].

GRWD1: Glutamate-rich WD repeat containing-1 (GRWD1), a chromatin regulator overexpressed in multiple cancers, inhibits p53 activation through RPL11 [ 176 , 177 , 178 ]. Stress-induced GRWD1 translocation to the nucleoplasm disrupts the RPL11-MDM2 interaction, suppressing p53 activation, while GRWD1 can also bind the p53 DNA-binding domain to modulate transcriptional activity [ 179 , 180 , 181 ].

MYBBP1A: MYB-binding protein-1A (MYBBP1A), which is normally nucleolar through rRNA binding, relocalises to the nucleoplasm upon stress, where it cooperates with RPL5 and RPL11 to enhance p53 acetylation through p300 recruitment [ 182 , 183 , 184 ].

RPS26, RPL26, and RPS3: RPS26 enhances p53 acetylation by complexing with p53 and p300 following DNA damage, RPL26 binds the 5′ UTR of TP53 mRNA to promote translation after DNA damage, and RPS3 protects p53 from MDM2-mediated ubiquitination [ 154 , 159 , 185 ]. Together, these observations indicate that RPs regulate p53 not only through MDM2 inhibition but also at the level of translation and post-translational modification.

NPM1, p14 ARF , and nucleolar regulators: Under basal conditions, NPM1 stabilises alternative reading frame protein (p19 ARF in mouse, p14 ARF in human) in the nucleolus [ 186 ]. Upon stress, p14 ARF relocates to the nucleoplasm and binds MDM2 to inhibit its activity, while NPM1 also modulates p53-MDM2 interactions in the nucleus [ 186 , 187 , 188 ]. NPM1 and p14 ARF form feedback loops involving MDM2, and their dysregulation can suppress p53 signalling [ 189 , 190 ]. Additional nucleolar proteins, including SRSF1, PAK1IP1, CSIG, and nucleostemin, also interact with MDM2 under stress [ 191 , 192 , 193 , 194 ].

AKT-MDM2 regulation: Pim-1 proto-oncogene, serine/threonine kinase (PIM1) phosphorylates AKT at Ser473, enabling AKT-mediated phosphorylation and activation of MDM2 to promote p53 degradation [ 195 , 196 ]. RPS19 depletion destabilises PIM1, reducing AKT phosphorylation and inactivating MDM2, thereby stabilising p53 [ 196 , 197 ].

NCL: NCL modulates p53 expression by regulating TP53 mRNA translation and relocalising under stress to influence replication-associated processes [ 185 , 198 , 199 ].

ASK1/p38 signalling: Ribosomal stress activates apoptosis signal-regulating Kinase 1 (ASK1)/p38 signalling to promote p53 phosphorylation and G1 arrest [ 200 ].

Collectively, these studies demonstrate that p53 stabilisation is governed by a multilayered network extending beyond the RP-MDM2 axis, integrating translational, post-translational, and signalling-based inputs. A key unresolved question is how these pathways are prioritised and coordinated across different stress contexts to determine p53-dependent cell fate outcomes.

5.1.3. Mechanistic Determinants and Stress Specificity of the p53-Dependent Nucleolar Surveillance Pathway

Despite extensive study, the mechanisms underlying the p53-dependent NSP remain incompletely resolved, particularly the factors required for activation. To address this, a functional genomic screen conducted by our group identified components required for NSP-mediated p53 stabilisation in response to nucleolar stress induced by RPS19 depletion [ 32 ]. The screen confirmed the essential roles of RPL5 and RPL11, whilst also identifying several new candidates, most notably HEATR3 , a factor essential for 60S subunit maturation and 5S-RNP biogenesis, whose biallelic loss-of-function variants are associated with Diamond–Blackfan Anaemia Syndrome (DBAS) [ 32 , 33 ]. In contrast, several previously reported regulators of p53 stabilisation, including PICT-1, MYBBP1A, NPM1, and SRSF1, were not identified as essential NSP components, suggesting tissue- or context-specific roles [ 32 ]. To assess the breadth of stressors that activate the p53-dependent NSP, cells were exposed to diverse genetic, physiological, and pharmacological insults [ 32 ]. Most nuclear and genetic perturbations stabilise p53 through the 5S-RNP-MDM2 axis, whereas proteotoxic stressors acted independently of this pathway [ 32 ]. These findings support Rubbi and Milner’s hypothesis that the nucleolus functions as a universal stress sensor that maintains p53 homeostasis in response to diverse cellular perturbations [ 32 , 123 ].

5.2. p53-Independent Nucleolar Surveillance Pathways

While the p53-dependent NSP is the most extensively described pathway, p53-independent mechanisms have also been reported, involving diverse effector proteins and signalling routes. These are summarised below and in Figure 6 .

E2F-1 regulation: In p53-null cells, inhibition of rRNA synthesis by RNA polymerase I subunit A ( POLR1A ) knockdown reduces E2F transcription factor 1 (E2F-1) levels through RPL11-pRb-dependent sequestration of MDM2, leading to Skp1-Cullin-1-F-box (SCF) protein containing Skp2 complex (SCF Skp2 )-mediated E2F-1 degradation and G1 arrest [ 201 ]. RPL3 similarly induces arrest by disrupting PARP1, E2F-1 interactions and repressing cyclin D1 expression, while also exerting pro-apoptotic and anti-autophagy functions [ 202 , 203 , 204 , 205 ]. RPS3 can also induce apoptosis through E2F-1, an effect suppressed by AKT-mediated phosphorylation of RPS3, which disrupts the RPS3-E2F-1 interaction [ 206 ].

p21 induction and mitochondrial regulation: RPL3 activates ERK/specificity protein 1 (Sp1) signalling to upregulate p21 in p53-null cells and represses cystathionine-β-synthase (CBS) expression to promote mitochondrial apoptosis under fluorouracil (5-FU) stress [ 205 , 207 , 208 , 209 ].

NF-κB pathway: Nucleolar disruption activates NF-κB through CDK4 inhibition and RRN3 degradation [ 210 , 211 ]. RPL3 stabilises IκBα, suppressing NF-κB signalling, while phospho-RPS3 enhances NF-κB pro-survival activity [ 212 , 213 ].

RP-mediated regulation of c-Myc: Multiple RPs regulate c-Myc expression to control cell growth. RPL11 and RPS14 bind c-Myc protein to block TRRAP recruitment and promote MYC mRNA decay through recruitment of the miRISC complex [ 214 , 215 ]. RPL5 and RPL11 also cooperate with RISC to suppress MYC mRNA expression [ 216 ].

PIM1 destabilisation and cell cycle arrest: PIM1 destabilises under ribosomal stress, which reduces p27 phosphorylation and induces cell cycle arrest in p53-null cells [ 197 ].

BAX-mediated apoptosis: In cells lacking p53, NPM relocalises to sequester BCL2-associated X protein (BAX) and suppress apoptosis [ 217 ]. Peter Pan homolog (PPAN), required for rRNA maturation, undergoes caspase-dependent degradation following stress, destabilising NPM and UBF while activating BAX-mediated apoptosis [ 218 ].

CHK1/2 and ATM/ATR activation and cell cycle arrest: In p53-null models, Pol I inhibition by CX-5461 activates CHK1/2 and G2/M arrest [ 219 ]. Furthermore, alkylating agents upregulate p14 ARF and trigger ATM/ATR activation, causing G2 arrest [ 220 ].

TAp73 stabilisation: RPL5 and RPL11 also interact with p53 homolog TAp73 to promote S phase arrest and apoptosis independently of p53 and MDM2 [ 221 ].

Collectively, these studies demonstrate that nucleolar stress responses are not confined to the canonical MDM2-p53 axis but instead involve a broad network of stress effectors that enable p53-independent surveillance. However, how these pathways are integrated and their relative contributions across different cellular and stress contexts remain unclear.

6. The Nucleolus in Disease

Given its central roles in RiBi and coordination of cellular stress responses, the nucleolus is essential for maintaining cellular homeostasis. Consequently, perturbations to nucleolar function can profoundly disrupt cellular physiology and contribute to pathological outcomes [ 222 ]. The relationship between the nucleolus and disease has been recognised by pathologists for over a century, with altered nucleolar morphology and number serving as disease biomarkers [ 223 ]. Reflecting its broad functional scope, nucleolar dysfunction is implicated in diverse diseases, including cancer, ribosomopathies, premature ageing, neurodegeneration, immune dysfunction, and viral infection [ 222 ]. The following sections discuss the roles of the nucleolus across these disease contexts.

6.1. Cancer

6.1.1. Nucleolar Hypertrophy and Elevated Ribosome Biogenesis

Aberrant increases in nucleolar number and size, reflecting elevated RiBi, have been recognised as a cancer hallmark since before the 1900s and correlate with poor prognosis across tumour types [ 223 , 224 , 225 ]. The importance of elevated RiBi to tumour growth is well established, with early evidence from an Eμ-Myc-driven Burkitt lymphoma mouse model demonstrating that excessive Pol I-mediated rDNA transcription is a critical driver of malignant transformation [ 226 , 227 , 228 ]. Accordingly, hyperactivated RiBi constitutes a core feature of sustained proliferative signalling in cancer [ 229 ].

6.1.2. Pathways Driving Hyperactivated Ribosome Biogenesis

In cancer cells, hyperactivated RiBi primarily arises from disruption of tumour suppressors, such as PTEN, pRb, and p53, and activation of oncogenic pathways, including PI3K/AKT/mTOR, RAS/RAF/ERK, and c-Myc ( Figure 3 ) [ 42 , 63 , 230 , 231 , 232 , 233 ]. These converge to upregulate Pol I transcription by increasing expression of Pol I subunits and transcription factors such as UBF and RRN3, and in some contexts, by activating previously silent rDNA repeats [ 227 , 234 ]. Consistent with this, PTEN loss or PIK3CA activation occurs in about one-third of sporadic tumours [ 235 , 236 ], RAF and RAS are mutated in ~6–7% and ~30% of cancers, respectively [ 237 , 238 ], and MYC is amplified or dysregulated in over 70% of malignancies [ 63 , 239 ].

6.1.3. Ribosomal Protein Dysregulation in Cancer

Consistent with elevated RiBi, overexpression of specific RPs correlates with poor prognosis across multiple cancers, including RPL35 and RPL15 in breast cancer, RPS20 and RPS11 in glioblastoma, and RPLP2, RPLP1 and RPLP0 in ovarian cancer [ 240 , 241 , 242 ]. Conversely, somatic mutations or deletions occur in several RP genes across diverse sporadic cancers, highlighting a complex and context-dependent role for RPs in tumorigenesis [ 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 ]. Extra-ribosomal functions of RPs may further contribute to oncogenesis; for example, loss of RPs that repress c-Myc expression, such as RPS14, RPL5, and RPL11, may promote malignant transformation, as demonstrated in lymphoma models with Rpl11 haploinsufficiency [ 215 , 216 , 250 , 251 , 252 ].

6.1.4. Evasion of the Nucleolar Surveillance Pathway

Malignant cells are frequently exposed to stressors that activate NSP responses, suggesting that suppression of NSP-induced p53 activation may confer a selective advantage during malignant transformation [ 32 , 253 ]. Consistent with this, TP53 is the most frequently mutated gene in cancer, with alterations present in ~50% of tumours [ 254 ]; while this enables evasion of p53-dependent NSP responses, p53-independent NSP pathways may remain active. Supporting a model of NSP-dependent selection pressure, heterozygous deletions or inactivating mutations in RP genes occur in ~43% of human cancers, almost exclusively in tumours harbouring TP53 mutations, and are underrepresented in TP53 wild-type cancers [ 243 , 255 ]. These observations suggest that sustained NSP activation triggered by RP depletion is incompatible with malignant transformation unless p53 signalling is inactivated [ 32 , 255 ].

6.2. Ribosomopathies

Ribosomopathies are a group of largely developmental disorders caused by genetic abnormalities that impair RiBi and function (detailed in Table 1 ) [ 256 , 257 ]. These disorders arise from disruptions at multiple stages of RiBi, including rDNA transcription, rRNA processing, and/or ribosomal subunit assembly.

Diamond–Blackfan Anaemia Syndrome (DBAS), a ribosomopathy first described almost a century ago, is predominantly caused by RP haploinsufficiency, most commonly in RPS19 (~25% of cases), with biallelic variants in HEATR3 recently identified as an additional causative lesion [ 33 , 258 , 259 ]. Several other congenital syndromes have since been linked to impaired RiBi, including Shwachman–Diamond Syndrome (SDS), primarily caused by loss-of-function mutations in the 60S maturation factor SBDS [ 260 ]; myelodysplastic neoplasm with low blast and isolated del(5q) (MDS-5q), resulting from deletion of the long arm of chromosome 5, encompassing 40 genes including RPS14 , CSNK1A1 , EGR1 , HSPA8 , miR-145, and miR-146a [ 261 ]; Treacher Collins Syndrome (TCS), caused by mutations in the rRNA transcription and processing factor TCOF1 or in Pol I subunits POLR1B , POLR1C , or POLR1D [ 262 ]; X-linked Dyskeratosis Congenita (DC), resulting from variants in DKC1 , which catalyses rRNA pseudouridylation [ 263 ]; Bowen–Conradi Syndrome (BCS), caused by mutations in the RNA methyltransferase and 40S biogenesis factor EMGI [ 264 ]; Cartilage-Hair Hypoplasia (CHH), caused by mutations in RMRP , which functions in pre-rRNA processing [ 265 ]; North American Indian childhood cirrhosis (NAIC), resulting from mutations in UTP4/CIRH1A , a pre-rRNA processing factor [ 266 ]; and acrofacial dysostosis, Cincinnati type, caused by loss-of-function mutations in the Pol I subunit POLR1A [ 267 ].

Additionally, less common ribosomopathies have been linked to mutations in RP genes and RiBi factors (e.g., RPSA , RPS23 , RPL10 , RPL13 , RPL21 , AIRIM, RBM28 , BMSI, and TAF1A ), further emphasising that disruption of diverse components of the ribosome production pathway can converge on pathological phenotypes [ 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 ].

6.2.1. Clinical Features and Pathogenic Mechanisms of Ribosomopathies

Despite arising from ubiquitous defects in RiBi, ribosomopathies manifest with striking tissue specificity, most commonly involving bone marrow failure and craniofacial or skeletal abnormalities ( Table 1 ) [ 256 ]. How disruption of such a fundamental cellular process produces these selective phenotypes remains a central and unresolved question. Notably, ribosomopathies presenting with paediatric bone marrow failure, including DBAS, SDS, MDS-5q, X-linked DC, and CHH, are associated with a significantly increased risk of malignancy later in life, with overall cancer incidence estimated at 2.5- to 8.5-fold higher than in the general population and up to 200-fold for specific cancer types [ 284 , 297 , 314 , 315 , 316 , 317 , 318 ]. Below, we discuss current models of ribosomopathy pathogenesis and proposed mechanisms linking ribosome dysfunction to tissue-specific phenotypes and cancer susceptibility.

Mechanisms Underlying Tissue Specificity in Ribosomopathies

Several mechanisms have been proposed to explain the tissue-specific phenotypes observed in ribosomopathies, as outlined below.

Affected cell lineages and proliferative demand: A consistent feature of multiple ribosomopathies is the selective vulnerability of neural crest (NC)-derived tissues, resulting in craniofacial defects, intellectual disability, cardiac abnormalities, skin and pigmentation defects, and hearing loss ( Table 1 ) [ 259 , 260 , 262 , 263 ]. Ribosome levels decline during human neuroepithelial differentiation, although protein synthesis must be maintained above a minimum threshold to support cell fate specification and survival [ 283 ]. Differentiating cells may therefore be particularly vulnerable to perturbations in RiBi, with failure to meet this threshold during critical developmental windows potentially contributing to these neurodevelopmental phenotypes [ 283 ].

The haematopoietic system is also frequently affected ( Table 1 ), commonly presenting as bone marrow failure, likely reflecting the high proliferative demand and reliance on elevated protein synthesis in these cells [ 259 , 260 , 262 ]. However, the relative sparing of other highly proliferative tissues, such as the intestine, indicates that proliferative demand alone does not fully explain tissue specificity.

p53-driven pathogenesis: The hypo-proliferative phenotypes in ribosomopathies are thought to arise, at least in part, from aberrant activation of the p53-dependent NSP in response to impaired RiBi. Multiple animal and patient studies implicate p53 activation in disease phenotypes across several ribosomopathies ( Table 1 ), with partial phenotypic rescue observed upon p53 depletion [ 306 , 319 , 320 , 321 , 322 , 323 , 324 , 325 ]. Tissue specificity may reflect cell type-specific differences in p53 sensitivity. For example, NC progenitors exhibit heightened p53 sensitivity within defined developmental windows [ 137 , 326 ], and erythroid progenitors appear disproportionately sensitive to p53 stabilisation [ 321 , 322 , 324 , 327 ]. The mechanisms underlying this lineage-specific sensitivity remain incompletely understood. p53 also regulates erythroid progenitor and immature precursor proliferation [ 328 ]; therefore, in ribosomopathies with impaired erythropoiesis, aberrant activation may impair erythroblast expansion both by enhancing its anti-proliferative effects and by disrupting this normal regulatory role. Nevertheless, not all ribosomopathy phenotypes are p53-dependent; for example, biallelic HEATR3 variants cause DBAS through a p53-independent mechanism [ 33 ], indicating that p53-dependent NSP activation is a major but not exclusive driver of pathogenesis.

Oxidative stress: Oxidative stress has emerged as an additional contributor, with elevated ROS reported in DBAS, DC, and SDS [ 329 , 330 , 331 , 332 ]. In DBAS, impaired RiBi slows globin synthesis while heme production proceeds at a relatively normal rate, generating excess free heme that promotes ROS production, lipid peroxidation, and apoptosis in erythroid cells [ 329 , 333 ]. Distinct mechanisms also contribute in other contexts. For example, in SDS, p53 activation in niche mesenchymal cells triggers secretion of inflammatory mediators that induce oxidative stress in neighbouring haematopoietic stem and progenitor cells (HSPCs) [ 334 ], while in TCS, impaired DNA damage repair in ROS-sensitive neuroepithelial and NC cells drives apoptosis and craniofacial pathology [ 131 , 136 , 335 ].

Translational dysregulation: Translational dysregulation may also contribute through two models. The specialised ribosome hypothesis proposes that RP defects alter ribosome composition and confer selective translational capacity [ 336 , 337 ], whereas the ribosome concentration hypothesis proposes that reduced ribosome availability selectively impairs translation of specific mRNAs [ 338 ]. In DBAS, impaired translation of GATA1 mRNA illustrates the latter mechanism [ 338 , 339 , 340 ]. Similarly, variants in the 60S biogenesis factor AIRIM reduce ribosome availability and disproportionately impair translation of specific transcripts, disrupting neuroepithelial fate commitment and survival, with these phenotypes partially rescued by enhancing mTOR signalling to increase global protein synthesis [ 283 ]. Additionally, these mechanisms likely intersect with p53-dependent responses, including p53-mediated suppression of cap-dependent translation via 4E-BP1 [ 341 ].

Collectively, these mechanisms illustrate how disrupted RiBi can alter cellular state in a highly context-dependent manner, giving rise to tissue-specific phenotypes. However, the relative contributions of these mechanisms, their potential interplay, and their causal roles in specific phenotypes remain key unresolved questions.

Cancer Susceptibility in Ribosomopathies

Several mechanisms may explain the shift from early hypo-proliferative phenotypes to later hyper-proliferation and cancer susceptibility in ribosomopathies associated with bone marrow failure, including somatic genetic rescue (SGR) and translational dysregulation.

Somatic genetic rescue: SGR involves the acquisition of mutations that mitigate germline defects and has been reported in SDS, DBAS, and MDS-5q [ 342 , 343 , 344 , 345 , 346 , 347 , 348 , 349 ]. While SGR can restore cellular fitness, it may also enable clonal expansion and increase the risk of malignant progression [ 342 , 343 ]. A key SGR event is selection for TP53 loss-of-function mutations driven by chronic p53 activation, enabling cells to evade apoptosis and cell cycle arrest [ 350 ]. This provides a proliferative advantage but removes a critical tumour suppressor barrier, thereby facilitating malignant transformation [ 350 ]. SGR can also restore RiBi defects directly; for example, in SDS, deletions reducing eIF6 dosage alleviate its inhibition of 60S maturation [ 342 , 345 , 351 ].

Translational dysregulation: Translational dysregulation may promote oncogenesis through “onco-ribosomes”, in which altered ribosome composition or fidelity biases translation toward oncogenic transcripts [ 350 ]. For example, RPS15 variants in chronic lymphocytic leukaemia (CLL) reduce translational fidelity [ 352 ], and RPL10 mutations in paediatric T-cell acute lymphoblastic leukaemia increase BCL-2 expression and JAK-STAT signalling [ 353 ].

Together, these mechanisms illustrate how initial defects in RiBi can create strong selective pressure for adaptations that restore growth while simultaneously lowering barriers to malignant transformation.

6.3. Other Nucleolus-Associated Pathologies

Beyond cancer and ribosomopathies, nucleolar dysfunction is implicated in premature ageing syndromes, neurodegenerative disorders, and infectious and immune conditions, as outlined below.

6.3.1. Ageing and Neurodegeneration

Studies of premature ageing syndromes and neurodegenerative disorders support a link between ageing, neurodegeneration, and altered nucleolar morphology and function [ 354 , 355 ], consistent with longstanding hypotheses implicating rDNA instability in cellular senescence and ageing [ 93 , 356 ]. Premature ageing syndromes caused by defects in DNA repair, including Cockayne syndrome (CS) and Werner syndrome (WS), show reduced nucleolar activity associated with impaired rDNA transcription [ 357 , 358 ]. In contrast, Hutchinson–Gilford progeria syndrome exhibits enlarged nucleoli driven by increased rDNA transcription and RiBi [ 359 ]. These observations indicate that both reduced and dysregulated nucleolar activity can contribute to ageing-associated phenotypes.

Many neurodegenerative diseases display nucleolar abnormalities resembling those in CS and WS. Nucleolar disruption is observed in Parkinson’s disease (PD) [ 360 ], and Rrn3 deletion in mouse dopaminergic neurons induces a PD-like phenotype with p53-dependent apoptosis [ 361 ]. Reduced nucleolar size, function, and translational capacity have also been reported in Alzheimer’s disease (AD) [ 362 , 363 ]. Heterozygous gain-of-function UBTF mutations are linked to childhood neuroregression syndrome [ 364 ]. Familial amyotrophic lateral sclerosis (ALS) driven by C9ORF72 mutations displays enlarged nucleoli associated with accumulation of toxic peptides and impaired RiBi and translation, suggesting nucleolar enlargement reflects stress rather than increased RiBi [ 365 , 366 , 367 , 368 ]. Nucleolar dysfunction has also been implicated in Huntington’s disease (HD), where post-translational UBF modifications reduce rDNA transcription, contributing to striatal dysfunction and neurodegeneration [ 369 , 370 , 371 ].

Across these conditions, nucleolar dysfunction converges on impaired proteostasis, stress signalling, and neuronal survival, highlighting a shared mechanistic link between RiBi dysregulation and neurodegeneration.

6.3.2. Infectious and Immune Disease

The nucleolus also contributes to host responses during viral and bacterial infections and may influence autoimmune disorders, as outlined below.

Viral Infection

Interactions between viruses and the nucleolus have been recognised for decades [ 110 , 372 , 373 ]. Viruses exploit host cellular machinery, and the nucleolus, as a key regulator of RiBi, RNA metabolism, and stress responses, is a frequent target of viral manipulation [ 110 , 372 , 373 ].

Viral proteins often localise to the nucleolus via NoLS or chaperones, interacting with nucleolar components to facilitate transcription, RNA maturation, or particle assembly [ 110 , 372 ]. Infection can also drive redistribution of nucleolar proteins to the nucleoplasm or cytoplasm, while recruiting non-nucleolar factors into nucleoli to support viral replication [ 110 , 372 ]. Viruses may further reshape host cell physiology by altering cell cycle progression, apoptosis, and RiBi [ 110 ]. These processes are accompanied by pronounced changes in nucleolar morphology and composition, reflecting functional reprogramming of the nucleolus during infection [ 373 ].

These interactions are observed across diverse RNA and DNA viruses, including Flaviviridae (e.g., Hepatitis C virus), Coronaviridae (e.g., SARS coronavirus), Orthomyxoviridae (e.g., Influenza A), Retroviridae (e.g., HIV), and Herpesviridae (e.g., Epstein–Barr virus), indicating that nucleolar targeting is a conserved strategy to co-opt host cellular machinery [ 110 , 222 , 372 , 373 , 374 , 375 ].

Bacterial Infection

The nucleolus also participates in host immune responses to bacterial pathogens. NCL recruits Rrp6-exosomes to the nucleolus to degrade cytosine/uracil-rich inflammatory pre-mRNAs, limiting inflammatory gene expression [ 111 ]. Accordingly, Ncl depletion in mice leads to excessive inflammatory responses and lethality following bacterial lipopolysaccharide (LPS) exposure [ 111 ]. Staphylococcus aureus , Acinetobacter baumannii, and Legionella pneumophila infection, also induce changes in nucleolar number and morphology [ 109 ]. Together, these observations suggest that nucleolar function may undergo dynamic remodelling during host–pathogen interactions.

Autoimmune Disorders

The involvement of the nucleolus in autoimmune disease is an emerging area, with mechanistic links yet to be fully established. Dysregulated microRNA expression is a feature of multiple autoimmune disorders, including Sjögren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus (SLE), Hashimoto’s thyroiditis, and Graves’ disease, raising the possibility that microRNA-associated nucleolar pathways may contribute to autoimmune dysregulation, although a direct causal role has not been established [ 222 , 376 ]. Similarly speculative is the “X chromosome-nucleolus nexus”, which proposes that stress-induced nucleolar expansion may engulf and disrupt adjacent chromatin regions, with the inactive X chromosome (Xi) potentially being especially susceptible because of its close proximity to the nucleolus. This may destabilise Xi, leading to aberrant expression of normally silenced X-linked genes and Xi-associated Alu elements, which could trigger immune responses and contribute to the female bias observed in autoimmune disorders [ 377 , 378 , 379 ]. Additionally, nucleolar proteins, including NCL and FBL, possess autoantigenic properties, and their release during cell death may stimulate production of antinuclear autoantibodies (ANAs) [ 380 ]. While these observations collectively hint at a role for nucleolar dysfunction in immune dysregulation, the underlying mechanisms require further experimental validation.

Collectively, these findings establish the nucleolus as a functionally important contributor to a broad spectrum of human diseases and disorders, encompassing cancer, ribosomopathies, ageing, neurodegeneration, and immune conditions. The recurrence of nucleolar dysfunction across such diverse pathological contexts presents opportunities for therapeutic exploitation.

7. Therapeutically Targeting the Nucleolus in Disease

The preceding sections highlight the central role of nucleolar dysfunction in human pathologies, prompting interest in therapeutically targeting key nucleolar processes, particularly RiBi and the NSP. A variety of mechanisms have been explored to directly modulate nucleolar function, including agents that influence RNA polymerase transcription (such as Pol I destabilisers, Pol I elongation inhibitors, and Pol III and rRNA processing modulators), ribosome assembly, nucleolar structure, and signalling pathways closely linked to RiBi. These mechanisms have been recently reviewed [ 381 , 382 ], and while some will be discussed below in the context of specific disease settings, others will not be addressed in detail.

Cancer and ribosomopathies illustrate opposite extremes of nucleolar dysregulation. In many cancers, hyperactivated RiBi drives proliferation, whereas ribosomopathies feature impaired RiBi and, frequently, excessive p53-dependent NSP activation. Consequently, therapeutic strategies differ: in cancer, interventions aim to suppress RiBi and leverage NSP activity to limit proliferation or induce cancer cell apoptosis, while in ribosomopathies, treatments focus on mitigating downstream consequences, such as bone marrow failure, or restoring RiBi through DNA- or RNA-based genetic approaches. These strategies are discussed in the following sections.

7.1. Therapeutic Targeting of the Nucleolus in Cancer

7.1.1. Small-Molecule Inhibitors Targeting Pol I Activity

The established role of hyperactivated RiBi in malignant transformation has driven the development of agents designed to selectively inhibit this process [ 382 ]. These include small-molecule therapies directly targeting Pol I activity, including CX-3543 [ 383 , 384 ], BMH-21 [ 385 , 386 ], and CX-5461 (Pidnarulex) [ 227 , 387 , 388 , 389 ]. CX-3543 binds rDNA G-quadruplex (G4) structures and disrupts their interaction with NCL, thereby inhibiting Pol I activity [ 383 ]. BMH-21 intercalates into G4 and GC-rich regions, which are particularly abundant in rDNA, and promotes degradation of the Pol I subunit RPA194 [ 385 , 386 ]. CX-5461 has emerged as a leading agent and is discussed below.

7.1.2. CX-5461: Preclinical Activity, Clinical Evaluation, and Mechanism of Action

Preclinical Activity: Preclinical studies have demonstrated robust anti-cancer activity of CX-5461. In Acute Myeloid Leukaemia (AML) and lymphoma, CX-5461 selectively eliminates malignant cells via activation of the p53-dependent NSP and subsequent cell cycle arrest and apoptosis, where sensitivity correlated with p53 status and RiBi activity [ 219 , 227 ]. CX-5461 extends survival in p53-null AML models through late S and G2/M arrest/delay mediated by ATM/ATR and CHK1/CHK2 signalling [ 227 ]. Anti-cancer activity has been demonstrated across a broad range of solid and haematological malignancies, consistent with a general dependency on elevated RiBi in cancer cells [ 387 , 390 , 391 , 392 , 393 , 394 ].

Clinical Evaluation: Clinical evaluation of CX-5461 has confirmed its therapeutic potential. A completed Phase I trial in advanced haematologic malignancies and breast cancer demonstrated activity ( NCT02719977 ) [ 389 ]. Ongoing Phase Ib studies are assessing tolerability in solid tumours, including pancreatic, ovarian, and breast cancers ( NCT04890613 ). CX-5461 has received FDA fast-track designation for the treatment of DNA damage repair-deficient cancers [ 395 ].

Mechanism of Action: CX-5461 is a quinazolinone-derived small-molecule inhibitor of Pol I transcription, identified through functional screening for selective suppression of rDNA transcription [ 387 ]. It exhibits ~200-fold greater potency against Pol I relative to Pol II, acting primarily by disrupting SL1-dependent PIC formation at rDNA promoters, thereby blocking Pol I transcription initiation without directly affecting Pol II activity or global transcription [ 219 , 227 , 387 ]. Subsequent studies identified additional mechanisms, including G4 stabilisation, nucleolar R-loop formation, promoter escape inhibition, and topoisomerase II inhibition [ 391 , 392 , 396 , 397 , 398 , 399 , 400 ]. Topoisomerase II inhibition provides a plausible basis for the DNA damage signalling observed in some cellular contexts, consistent with ATM/ATR pathway activation [ 397 , 398 , 399 , 400 ]. However, the relative contribution of these mechanisms to its anti-cancer effects remains unresolved. Nevertheless, nucleolar stress signalling induced by Pol I transcription inhibition is likely the dominant driver of therapeutic efficacy [ 219 , 227 ].

Mutagenicity: Concerns regarding mutagenicity have been raised in in vitro studies reporting non-selective mutagenesis at levels exceeding environmental carcinogens [ 400 ]. However, these findings have not been reproduced across independent experimental systems, and clinical sequencing data in a Phase I trial showed no significant increase in mutational burden (ACTRN12613001061729). These observations indicate that clinical activity is not primarily driven by genotoxic mechanisms, and that the in vitro mutagenic effects likely reflect context-specific or off-target effects rather than an inherent property of Pol I inhibition.

7.1.3. Next-Generation Pol I Inhibitors: PMR-116

To address concerns around DNA damage and to enable improved therapeutic index and potential application in settings such as central nervous system malignancies, next-generation selective Pol I inhibitors with reduced off-target activation of DNA damage signalling have been developed, including PMR-116 [ 401 ]. PMR-116 arrests Pol I at the rDNA promoter, preventing promoter escape and reducing elongation, representing a more selective suppression of RiBi compared to the multi-mechanistic activity described for CX-5461 [ 401 ]. In preclinical models, it activates the p53-dependent NSP, delays cell cycle progression, and suppresses E2F and c-Myc signalling, with MYC -driven cancers being particularly sensitive [ 401 ]. Importantly, it does not induce CHK1/2 phosphorylation or global γH2AX foci formation, suggesting that PMR-116 mediates its anti-cancer effects independent of DNA damage [ 401 ]. Early Phase I data show on-target activity, with ~50% reduction in rRNA synthesis in peripheral blood cells 24 h post-treatment (CTRN12620001146987), and the compound has progressed to Phase II evaluation [ 402 ].

Together, these studies highlight that selective targeting of Pol I transcription can be refined to dissociate nucleolar stress signalling from DNA damage responses, providing a path toward effective and potentially less genotoxic cancer therapies.

7.2. Therapeutic Strategies for Ribosomopathies

7.2.1. Current Therapeutic Strategies

Bone marrow failure is the predominant cause of morbidity in both inherited and acquired ribosomopathies, arising from impaired RiBi that disrupts haematopoietic progenitor proliferation and survival [ 256 , 257 ]. Therapeutic strategies are primarily supportive and tailored to the specific cytopenias present, with the aim of maintaining haematopoiesis, reducing complications, and preserving organ function prior to consideration of curative therapy [ 403 ]. Importantly, most current therapies do not directly target nucleolar function or RiBi itself but instead aim to ameliorate downstream consequences of impaired RiBi, particularly cytopenias and organ dysfunction ( Table 1 ).

Anaemia: In DBAS, corticosteroids such as dexamethasone and prednisone are the first-line therapy, stimulating stress erythropoiesis and expansion of early erythroid progenitors [ 259 , 404 , 405 , 406 ]. Approximately 80% of patients initially respond, although only ~40% maintain long-term benefit, and ~20% are entirely refractory [ 407 , 408 ]. Chronic or high-dose steroid use carries risks including growth delays, osteoporosis, hypertension, cataracts, and immunosuppression [ 406 , 409 ]. In SDS, MDS-5q, and DC, anaemia is often managed with red blood cell transfusions; however, in MDS-5q, this may be progressively replaced by treatments such as retinoid, lenalidomide, and erythropoietin [ 403 ]. In CHH, severe anaemia requiring transfusion is uncommon [ 403 ]. These strategies are informed by disease-specific differences in haematopoiesis: DBAS is predominantly erythroid-restricted, whereas SDS, MDS-5q, DC, and CHH frequently present with multilineage marrow dysfunction [ 403 ].

Neutropenia: Neutropenia is prominent in SDS and can also occur in CHH [ 260 , 265 ]. Granulocyte colony-stimulating factor (G-CSF) is used to increase neutrophil counts and prevent infections, while haematopoietic stem cell transplantation (HSCT) is used to correct immunodeficiency [ 403 ]. Recurrent infections may exacerbate organ dysfunction, highlighting the need for early intervention [ 410 ].

Platelet Abnormalities: Platelet transfusions are indicated in severe thrombocytopenia, which can occur in SDS, DC, and CHH, while thrombocytosis can arise in MDS-5q, often alongside other cytopenias [ 265 , 295 , 410 , 411 ]. Accordingly, careful monitoring of platelet levels and related complications may be required in affected patients.

Multilineage Therapies: Supportive care in SDS often extends beyond marrow failure to address pancreatic insufficiency and nutritional deficiencies [ 403 , 412 ]. In MDS-5q, lenalidomide remains a well-established immunomodulatory therapy that can reduce transfusion dependence in many patients [ 261 ]. DBAS, SDS, TCS, and CHH patients may require management of craniofacial and skeletal abnormalities through reconstructive surgery [ 403 ].

While these interventions can partially correct cytopenias and improve quality of life, they do not address the underlying defect in RiBi or nucleolar function and are associated with long-term complications such as iron overload, endocrine dysfunction, infection, and cardiovascular disease [ 403 , 409 , 413 ]. This highlights a major therapeutic gap and the need for approaches that directly target nucleolar pathways.

7.2.2. Emerging Pharmacological Therapies

Several pharmacological agents targeting disease-relevant pathways are under clinical investigation or showing translational promise across the spectrum of ribosomopathies, particularly in DBAS, SDS, and DC. However, most emerging agents similarly act indirectly, targeting stress response or translational control pathways (e.g., p53 or mTOR signalling) rather than restoring nucleolar function per se .

Diamond–Blackfan Anaemia Syndrome: In DBAS, L-leucine, an mTOR activator, has been evaluated in early clinical studies and compassionate use settings, enhancing translation and erythropoiesis with improvements in haemoglobin and growth parameters without major adverse events [ 259 , 414 , 415 , 416 ]. Agents that modulate p53 signalling remain of interest; the FDA-approved calmodulin inhibitor trifluoperazine reduces p53 target activation and ameliorates anaemia in preclinical DBAS models ( NCT03966053 ) [ 417 ], prompting the development of next-generation compounds with improved safety [ 418 ]. The thrombopoietin receptor agonist eltrombopag has been evaluated to reduce toxic free heme arising from heme-globin imbalance in DBAS, showing modest haemoglobin improvement but causing dose-limiting thrombocytosis in some patients ( NCT04269889 ) [ 419 , 420 ].

Shwachman–Diamond Syndrome: Given the high prevalence of nonsense mutations in SBDS , Ataluren, a small-molecule that promotes ribosomal read-through of premature stop codons, was administered to three SDS patients carrying nonsense mutations under a compassionate use program [ 421 ]. Treatment restored SBDS protein function and alleviated both pancreatic and haematopoietic dysfunction, supporting nonsense suppression as a potential therapeutic strategy [ 421 ].

Dyskeratosis Congenita: For DC, androgen derivatives such as danazol and oxymetholone have demonstrated haematological improvement in clinical studies, increasing haemoglobin, granulocyte, and platelet levels, and are among the few pharmacological agents with broad lineage effects [ 422 , 423 ]. Given the defective telomere maintenance in DC, a telomere elongation gene therapy ( EXG34217 ) delivering Zinc finger and SCAN domain-containing 4 (ZSCAN4), a recombination-mediated telomere elongation factor, into mobilised CD34 + cells for autologous HSCT is under early clinical investigation ( NCT04211714 ) [ 424 ].

Future efforts may focus on developing small molecules that target ribosomal dysfunction (e.g., in the context of DBAS, modulators of RiBi, p53 activation, and proliferation in erythroid progenitors and precursors with the aim of rescuing erythropoiesis [ 425 , 426 ]) to improve treatment efficacy and reduce relapse. Collectively, these pharmacological strategies illustrate a growing pipeline of small-molecule and mechanism-targeted agents that move beyond symptom management toward pathway-directed intervention, although most remain in early clinical evaluation or preclinical development.

7.2.3. Allogeneic Haematopoietic Stem Cell Transplantation

Allogeneic HSCT remains the only potentially curative therapy for bone marrow failure in DBAS, SDS, MDS-5q, DC, and CHH [ 427 , 428 , 429 , 430 , 431 ]. HSCT restores multilineage haematopoiesis and can mitigate long-term complications of chronic supportive therapy [ 427 , 428 , 429 , 430 , 431 ]. Despite its curative potential, HSCT is associated with substantial morbidity and mortality, largely from infections and graft-versus-host disease (GVHD), and requires lifelong immunosuppression therapy [ 428 , 429 , 430 , 431 , 432 ]. Other complications include thrombotic microangiopathy, veno-occlusive disease, acute pancreatitis, EBV-associated lymphoproliferative disease, and secondary malignancies [ 428 , 429 , 430 , 431 , 432 ].

Ongoing clinical trials aim to improve HSCT safety and efficacy in ribosomopathies and related disorders through optimised conditioning and T- and B-cell depletion, including trials NCT04965597 (DBAS, SDS, other BMFS, haematologic neoplasms), NCT02928991 (DBAS, DC, SDS, other BMFS), NCT03513328 (DBAS, other BMFS, haemoglobinopathies, metabolic disorders, primary immunodeficiencies), NCT04099966 (DBAS, MDS, other BMFS, haematologic neoplasms, sickle cell disease), and NCT03653338 (DBAS, β-thalassemia, sickle cell disease). Nonetheless, the limitations of current HSCT regimes underscore the need for alternative approaches targeting the molecular lesions, with the goal of reducing toxicity, enhancing efficacy, and preventing secondary complications such as cancer.

7.3. DNA and RNA Therapeutic Approaches in Ribosomopathies and Cancer

Emerging DNA- and RNA-based therapies provide a framework for directly modulating nucleolar function and RiBi, with the potential to move beyond symptomatic management and address underlying molecular defects. These approaches may enable restoration of defective RP expression, tuning of nucleolar stress pathways, and selective targeting of nucleolar dependencies in cancer. While clinical data remain limited, early preclinical studies highlight their potential as mechanism-directed interventions. The following sections summarise current strategies and outline key challenges for their translation.

7.3.1. DNA-Based Therapeutic Strategies

DNA-based approaches aim for permanent or semi-permanent correction of pathogenic variants or haematopoietic regulators. This approach has been successfully utilised across a broad range of disease conditions [ 433 ], and in ribosomopathies, ex vivo lentiviral delivery of wild-type RPS19 has shown potential in rescuing erythropoiesis in RPS19 -deficient human HSPCs and mice [ 434 , 435 , 436 , 437 ]. Similarly, a lentiviral construct driving erythroid-specific GATA1 expression enhanced erythropoiesis in patient-derived HSPCs across diverse genotypes [ 438 ], reflecting observations that GATA1 mRNA levels are reduced across multiple DBAS genotypes [ 339 , 340 , 438 ]. CRISPR-based editing, including base and prime editors, offers correction of point mutations or small insertions or deletions while maintaining endogenous gene regulation and has shown promise in correcting RPS19 mutations in HSPCs [ 439 , 440 ]. A self-inactivating lentiviral vector carrying a functional RPS19 transgene is currently under clinical evaluation for RPS19 -deficient DBAS ( NCT07476183 ).

In malignancy, hyperactive RiBi represents a therapeutic vulnerability. Future DNA-based strategies may offer opportunities to restore dysregulated RiBi or selectively disrupt nucleolus-dependent proliferation. Candidate targets could include NPM1, RPs, and MYC , which are frequently overexpressed in cancers [ 63 , 240 , 241 , 242 , 249 ]. Approaches such as non-integrating vectors or in vivo gene editing could also provide opportunities for direct tumour targeting with reduced off-target risk.

7.3.2. RNA-Based Therapeutic Strategies

RNA-based therapies enable transient and tuneable modulation of protein expression and have been applied across diverse therapeutic modalities, including protein replacement, vaccines, immunotherapy, and gene editing, with applications across a wide range of diseases such as cancer, infectious, immune, haematological, metabolic, cardiovascular, respiratory, and neurological disorders [ 441 , 442 , 443 , 444 ]. RNA-based approaches are particularly useful when permanent genomic modification is undesirable or when delivery constraints limit DNA-based strategies. In the context of nucleolar disorders, RNA therapeutics could be employed to correct RiBi defects in ribosomopathies or selectively induce nucleolar stress in cancer cells.

mRNA-Based Protein Replacement and Gene Editing

Synthetic mRNA may replace defective RPs or nucleolar regulators, offering a temporary compensatory mechanism for mutations associated with ribosomopathies. Lipid nanoparticles (LNPs) enable efficient HSPC uptake in vivo and transient protein expression without genome integration [ 445 , 446 , 447 , 448 , 449 , 450 , 451 ]. mRNA approaches have corrected disease phenotypes in preclinical models of erythroid disorders, including haemophilia A [ 452 ] and B [ 453 ], thrombotic thrombocytopenic purpura [ 454 ], β-thalassemia [ 449 ], sickle cell disease [ 445 ], and Fanconi anaemia [ 448 ]. Although untested in ribosomopathies, this approach may provide a strategy to support ribosome assembly in HSPCs. Beyond protein replacement, mRNA can encode gene-editing machinery, enabling precise correction of pathogenic alleles [ 455 , 456 ]. mRNA-based platforms may also enable expression of non-genotoxic conditioning factors for HSCT; for example, by using transient expression of pro-apoptotic factors to selectively deplete HSPCs, reducing reliance on chemotherapy or irradiation [ 445 ].

In the context of cancer, mRNA-based strategies could restore tumour suppressor function or sensitise tumour cells to adjunct therapies [ 457 ]. In preclinical models, delivery of TP53 mRNA restored p53 protein expression in TP53 -null non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), suppressing tumour growth and increasing sensitivity to the mTOR inhibitor everolimus [ 458 ]. Trp53 mRNA has also been shown to enhance the efficacy of anti-PD-1 immunotherapy in HCC models by reshaping the immune tumour microenvironment, resulting in reduced tumour growth and improved survival [ 459 ]. Similarly, PTEN mRNA delivery restored functional PTEN and reversed the immunosuppressive tumour microenvironment in PTEN-deficient prostate tumours and melanoma [ 460 ], and lysine-specific demethylase 6A ( KDM6A ) mRNA inhibited metastasis in KDM6A -null bladder cancer models [ 461 ]. mRNA delivery could also be used to induce nucleolar stress in tumour cells, providing a potential strategy to exploit nucleolar dependencies in cancer.

RNA Editing

RNA-editing technologies, including RNA trans-splicing and base editing, may enable correction of mutant transcripts encoding nucleolar proteins without altering genomic DNA [ 462 , 463 ]. In ribosomopathies, such approaches could recover functional RP expression, while in cancer, they may enable correction of nucleolar driver mutations. Adenine base editors have been used to repair TP53 hotspot mutations in cancer cell lines from multiple tissues, restoring p53 tumour-suppressive programs and inhibiting cancer cell growth [ 464 ]. This platform has also corrected cancer-associated mutations in KRAS , PTEN , and SMAD4 [ 464 ]. Although largely proof-of-concept, even partial transcript correction could provide therapeutic benefit and act synergistically with chemotherapy [ 465 ]. Key challenges include delivery efficiency, off-target activity, and mutation-specific design, although advances in RNA delivery and editing are progressively addressing these issues [ 463 , 466 ].

ASO and siRNA-Based Therapeutic Strategies

Antisense oligonucleotides (ASOs) and siRNAs may provide transcript-level modulation of nucleolar proteins [ 467 ]. In ribosomopathies, ASOs could potentially correct aberrant splicing or reduce dominant-negative transcripts, although preclinical studies remain limited [ 468 ]. In nucleolus-driven cancers, future therapeutic strategies may employ siRNA-mediated knockdown of overexpressed nucleolar regulators, such as NPM1, RPs, and c-Myc, to induce nucleolar stress and impair tumour proliferation, with preclinical studies demonstrating efficacy in reducing oncogene expression [ 469 , 470 , 471 , 472 , 473 , 474 , 475 , 476 , 477 , 478 , 479 , 480 ]. However, no cancer siRNA therapies targeting nucleolar pathways have yet reached clinical approval.

Advantages of these approaches include high specificity, transient and tuneable effects, and compatibility with delivery platforms such as LNPs or GalNAc conjugates [ 467 , 474 , 480 , 481 ]. Limitations include efficient delivery to HSPCs or solid tumours, RNA stability, immunogenicity, and lack of clinical validation [ 467 , 474 , 480 , 481 ]. Future strategies may integrate ASO or siRNA therapies with mRNA replacement or DNA-based editing to simultaneously suppress pathogenic transcripts and restore protein function.

7.3.3. Delivery Challenges

Targeted delivery to the desired tissue and cell type remains a central challenge for both DNA- and RNA-based therapies [ 482 , 483 ]. In particular, HSPCs are difficult to access due to their low abundance, protective niches, and sensitivity to manipulation, while selective targeting of tumour cells requires high precision [ 482 , 483 , 484 ]. Recent advances are nevertheless improving targeted delivery to these cell types; LNPs engineered with cell-specific ligands can achieve in vivo transfection without ex vivo manipulation. For example, modified Fancc mRNA delivered via LNPs restored HSPC expansion in Fancc –/– mice [ 448 ]. Similarly, CD117- or CD45-targeted antibody-conjugated and antibody-free LNPs have achieved HSPC transfection in preclinical models, highlighting the potential for non-genotoxic in vivo delivery [ 445 , 446 , 447 , 448 , 449 , 450 , 451 ].

DNA- and RNA-based therapies provide a promising route to address ribosomal dysfunction in ribosomopathies and exploit nucleolus-dependent vulnerabilities in cancer, with early preclinical studies supporting their potential to restore RP expression and modulate nucleolar stress pathways. However, translating this potential will require advances in targeted delivery, expression durability, immune tolerance, and scalable production [ 442 , 463 , 467 , 483 ]. Addressing these constraints will be critical for realising the broader clinical potential of DNA- and RNA-based therapeutic platforms, including their application to disorders of nucleolar function and cancers in which the nucleolus represents a tractable therapeutic target.

8. Conclusions and Future Perspectives

The nucleolus has evolved from being viewed as a specialised site of ribosome production to a central regulator of cellular homeostasis. Across the areas covered in this review, a consistent theme emerges: RiBi is tightly integrated with growth and stress signalling, and disruption of this coupling has direct consequences for cell fate. The nucleolus functions accordingly as a sensor and integrator of cellular conditions, linking rDNA transcription to nucleolar surveillance pathways and broader stress-response networks.

This provides a unifying model for its role in disease. In cancer, elevated RiBi supports proliferative and metabolic demand; in ribosomopathies, impaired ribosome production engages stress pathways that constrain cell growth or survival. These opposing phenotypes reflect a shared underlying principle: cellular fitness is acutely sensitive to changes in ribosome output, with the NSP acting as a central mediator. The nucleolus therefore sits upstream of many of the pathological phenotypes described, rather than arising as a secondary consequence of them.

Several important questions remain unresolved, including how nucleolar organisation and function are remodelled across cellular states, how distinct nucleolar outputs are specified in a context-dependent manner, and the extent to which p53-independent pathways contribute to pathology. Resolving these questions will be essential for translating mechanistic insight into therapeutic progress.

The therapeutic landscape is advancing. Current approaches largely suppress elevated RiBi in cancer or compensate for downstream defects in ribosomopathies, but emerging strategies indicate that more direct and selective modulation of nucleolar function is achievable. Small-molecule inhibitors of Pol I transcription, gene-editing strategies, and RNA-based approaches offer complementary routes to manipulate nucleolar pathways, and advances in delivery are making cell-type-specific intervention increasingly feasible. Improved methods to resolve nucleolar composition and function are concurrently revealing tractable therapeutic vulnerabilities.

The nucleolus is not a passive downstream effector of disease but an underexploited point of control. The next step is to move beyond broad suppression or compensation towards mechanism-informed, context-specific modulation of nucleolar activity, and the tools to do so are within reach. As mechanistic understanding improves, interventions that act directly on RiBi and nucleolar surveillance pathways offer a credible and increasingly realistic path to greater therapeutic specificity and durability across a range of disease settings.

Acknowledgments

Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 and Figure 6 were created in BioRender. George, A. (2026) ( https://BioRender.com/uojob9s , https://BioRender.com/hzgi6iv , https://BioRender.com/m9jej8h , https://BioRender.com/mco55uc , https://BioRender.com/92qvf5s , https://BioRender.com/n5xym3h ). During the preparation of this manuscript, the authors used Claude (Anthropic) and ChatGPT (GPT-5.5; OpenAI) for grammatical and structural checking.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Author Contributions

O.D. wrote the original draft of the manuscript and prepared all figures. J.X., N.H., R.F., R.D.H., and A.J.G. reviewed and edited the manuscript. A.J.G. supervised the work. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analysed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Mangan H. Gailin M.O. McStay B. Integrating the genomic architecture of human nucleolar organizer regions with the biophysical properties of nucleoli FEBS J. 2017 284 3977 3985 10.1111/febs.14108 28500793

2. McStay B. Nucleolar organizer regions: Genomic ‘dark matter’ requiring illumination Genes Dev. 2016 30 1598 1610 10.1101/gad.283838.116 27474438 PMC4973289

3. Lafontaine D.L.J. Riback J.A. Bascetin R. Brangwynne C.P. The nucleolus as a multiphase liquid condensate Nat. Rev. Mol. Cell Biol. 2021 22 165 182 10.1038/s41580-020-0272-6 32873929

4. Yao R.W. Xu G. Wang Y. Shan L. Luan P.F. Wang Y. Wu M. Yang L.Z. Xing Y.H. Yang L. Nascent Pre-rRNA Sorting via Phase Separation Drives the Assembly of Dense Fibrillar Components in the Human Nucleolus Mol. Cell 2019 76 767 783.e11 10.1016/j.molcel.2019.08.014 31540874

5. Stenstrom L. Mahdessian D. Gnann C. Cesnik A.J. Ouyang W. Leonetti M.D. Uhlen M. Cuylen-Haering S. Thul P.J. Lundberg E. Mapping the nucleolar proteome reveals a spatiotemporal organization related to intrinsic protein disorder Mol. Syst. Biol. 2020 16 e9469 10.15252/msb.20209469 32744794 PMC7397901

6. Nemeth A. Conesa A. Santoyo-Lopez J. Medina I. Montaner D. Peterfia B. Solovei I. Cremer T. Dopazo J. Langst G. Initial genomics of the human nucleolus PLoS Genet. 2010 6 e1000889 10.1371/journal.pgen.1000889 20361057 PMC2845662

7. Mitrea D.M. Cika J.A. Stanley C.B. Nourse A. Onuchic P.L. Banerjee P.R. Phillips A.H. Park C.G. Deniz A.A. Kriwacki R.W. Self-interaction of NPM1 modulates multiple mechanisms of liquid-liquid phase separation Nat. Commun. 2018 9 842 10.1038/s41467-018-03255-3 29483575 PMC5827731

8. Stults D.M. Killen M.W. Pierce H.H. Pierce A.J. Genomic architecture and inheritance of human ribosomal RNA gene clusters Genome Res. 2008 18 13 18 10.1101/gr.6858507 18025267 PMC2134781

9. Parks M.M. Kurylo C.M. Dass R.A. Bojmar L. Lyden D. Vincent C.T. Blanchard S.C. Variant ribosomal RNA alleles are conserved and exhibit tissue-specific expression Sci. Adv. 2018 4 eaao0665 10.1126/sciadv.aao0665 29503865 PMC5829973

10. Smirnov E. Chmurciakova N. Liska F. Bazantova P. Cmarko D. Variability of Human rDNA Cells 2021 10 196 10.3390/cells10020196 33498263 PMC7909238

11. Gonzalez-Arzola K. The nucleolus: Coordinating stress response and genomic stability Biochim. Biophys. Acta Gene Regul. Mech. 2024 1867 195029 10.1016/j.bbagrm.2024.195029 38642633

12. Hori Y. Engel C. Kobayashi T. Regulation of ribosomal RNA gene copy number, transcription and nucleolus organization in eukaryotes Nat. Rev. Mol. Cell Biol. 2023 24 414 429 10.1038/s41580-022-00573-9 36732602

13. Srivastava R. Srivastava R. Ahn S.H. The Epigenetic Pathways to Ribosomal DNA Silencing Microbiol. Mol. Biol. Rev. 2016 80 545 563 10.1128/MMBR.00005-16 27250769 PMC4981667

14. Caburet S. Conti C. Schurra C. Lebofsky R. Edelstein S.J. Bensimon A. Human ribosomal RNA gene arrays display a broad range of palindromic structures Genome Res. 2005 15 1079 1085 10.1101/gr.3970105 16024823 PMC1182220

15. Walker B.M. Chung J.Y. Pascual H.G. Adala J.D. Knutson B.A. Molecular Mechanisms of RNA Polymerase I Transcription in Health and Disease: An Overview Mol. Cell. Biol. 2026 46 524 545 10.1080/10985549.2026.2628826 41729064

16. Sun L. Chen M. Wang X. RNA Polymerase III-Transcribed RNAs in Health and Disease: Mechanisms, Dysfunction, and Future Directions Int. J. Mol. Sci. 2025 26 5852 10.3390/ijms26125852 40565315 PMC12193147

17. Ojha S. Malla S. Lyons S.M. snoRNPs: Functions in Ribosome Biogenesis Biomolecules 2020 10 783 10.3390/biom10050783 32443616 PMC7277114

18. Schier A.C. Taatjes D.J. Structure and mechanism of the RNA polymerase II transcription machinery Genes Dev. 2020 34 465 488 10.1101/gad.335679.119 32238450 PMC7111264

19. Dorner K. Ruggeri C. Zemp I. Kutay U. Ribosome biogenesis factors-from names to functions EMBO J. 2023 42 e112699 10.15252/embj.2022112699 36762427 PMC10068337

20. Abraham K.J. Khosraviani N. Chan J.N.Y. Gorthi A. Samman A. Zhao D.Y. Wang M. Bokros M. Vidya E. Ostrowski L.A. Nucleolar RNA polymerase II drives ribosome biogenesis Nature 2020 585 298 302 10.1038/s41586-020-2497-0 32669707 PMC7486236

21. Steiner A. Favre S. Mack M. Hausharter A. Pillet B. Hafner J. Mitterer V. Kressler D. Pertschy B. Zierler I. Dissecting the Nuclear Import of the Ribosomal Protein Rps2 (uS5) Biomolecules 2023 13 1127 10.3390/biom13071127 37509163 PMC10377357

22. Lu J. Wu T. Zhang B. Liu S. Song W. Qiao J. Ruan H. Types of nuclear localization signals and mechanisms of protein import into the nucleus Cell Commun. Signal. 2021 19 60 10.1186/s12964-021-00741-y 34022911 PMC8140498

23. Martin R.M. Ter-Avetisyan G. Herce H.D. Ludwig A.K. Lattig-Tunnemann G. Cardoso M.C. Principles of protein targeting to the nucleolus Nucleus 2015 6 314 325 10.1080/19491034.2015.1079680 26280391 PMC4615656

24. Watkins N.J. Bohnsack M.T. The box C/D and H/ACA snoRNPs: Key players in the modification, processing and the dynamic folding of ribosomal RNA Wiley Interdiscip. Rev. RNA 2012 3 397 414 10.1002/wrna.117 22065625

25. Aubert M. O’Donohue M.F. Lebaron S. Gleizes P.E. Pre-Ribosomal RNA Processing in Human Cells: From Mechanisms to Congenital Diseases Biomolecules 2018 8 123 10.3390/biom8040123 30356013 PMC6315592

26. Dogra P. Ferrolino M.C. Khatun S. Miao Q. Tolbert M. Pitre A. Pruett-Miller S.M. Tripathi S. Baggett D.W. John J. Granular component sub-phases direct ribosome biogenesis in the nucleolus Mol. Cell 2026 in press 10.1016/j.molcel.2026.06.035 42456652 PMC13435773

27. Vanden Broeck A. Klinge S. Principles of human pre-60S biogenesis Science 2023 381 eadh3892 10.1126/science.adh3892 37410842

28. Singh S. Vanden Broeck A. Miller L. Chaker-Margot M. Klinge S. Nucleolar maturation of the human small subunit processome Science 2021 373 eabj5338 10.1126/science.abj5338 34516797 PMC8744464

29. Bohnsack K.E. Bohnsack M.T. Uncovering the assembly pathway of human ribosomes and its emerging links to disease EMBO J. 2019 38 e100278 10.15252/embj.2018100278 31268599 PMC6600647

30. Sloan K.E. Bohnsack M.T. Watkins N.J. The 5S RNP couples p53 homeostasis to ribosome biogenesis and nucleolar stress Cell Rep. 2013 5 237 247 10.1016/j.celrep.2013.08.049 24120868 PMC3808153

31. Nicolas E. Parisot P. Pinto-Monteiro C. de Walque R. De Vleeschouwer C. Lafontaine D.L. Involvement of human ribosomal proteins in nucleolar structure and p53-dependent nucleolar stress Nat. Commun. 2016 7 11390 10.1038/ncomms11390 27265389 PMC4897761

32. Hannan K.M. Soo P. Wong M.S. Lee J.K. Hein N. Poh P. Wysoke K.D. Williams T.D. Montellese C. Smith L.K. Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway Cell Rep. 2022 41 111571 10.1016/j.celrep.2022.111571 36323262 PMC9647041

33. O’Donohue M.F. Da Costa L. Lezzerini M. Unal S. Joret C. Bartels M. Brilstra E. Scheijde-Vermeulen M. Wacheul L. De Keersmaecker K. HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia Blood 2022 139 3111 3126 10.1182/blood.2021011846 35213692 PMC9136880

34. Ruland J.A. Krüger A.M. Dörner K. Bhatia R. Wirths S. Poetes D. Kutay U. Siebrasse J.P. Kubitscheck U. Nuclear export of the pre-60S ribosomal subunit through single nuclear pores observed in real time Nat. Commun. 2021 12 6211 10.1038/s41467-021-26323-7 34707094 PMC8551241

35. Junod S.L. Tingey M. Kelich J.M. Goryaynov A. Herbine K. Yang W. Dynamics of nuclear export of pre-ribosomal subunits revealed by high-speed single-molecule microscopy in live cells iScience 2023 26 107445 10.1016/j.isci.2023.107445 37599825 PMC10433129

36. Khatter H. Myasnikov A.G. Natchiar S.K. Klaholz B.P. Structure of the human 80S ribosome Nature 2015 520 640 645 10.1038/nature14427 25901680

37. Brito Querido J. Diaz-Lopez I. Ramakrishnan V. The molecular basis of translation initiation and its regulation in eukaryotes Nat. Rev. Mol. Cell Biol. 2024 25 168 186 10.1038/s41580-023-00624-9 38052923

38. Dever T.E. Dinman J.D. Green R. Translation Elongation and Recoding in Eukaryotes Cold Spring Harb. Perspect. Biol. 2018 10 a032649 10.1101/cshperspect.a032649 29610120 PMC6071482

39. Shore D. Albert B. Ribosome biogenesis and the cellular energy economy Curr. Biol. 2022 32 R611 R617 10.1016/j.cub.2022.04.083 35728540

40. Piazzi M. Bavelloni A. Gallo A. Faenza I. Blalock W.L. Signal Transduction in Ribosome Biogenesis: A Recipe to Avoid Disaster Int. J. Mol. Sci. 2019 20 2718 10.3390/ijms20112718 31163577 PMC6600399

41. Lawrence I.R. Sutton E.C. Bhaskar S. Baserga S.J. Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus Mol. Cell 2026 86 469 490 10.1016/j.molcel.2026.01.007 41610859 PMC12866967

42. Glaviano A. Foo A.S.C. Lam H.Y. Yap K.C.H. Jacot W. Jones R.H. Eng H. Nair M.G. Makvandi P. Geoerger B. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer Mol. Cancer 2023 22 138 10.1186/s12943-023-01827-6 37596643 PMC10436543

43. Mukherjee R. Vanaja K.G. Boyer J.A. Gadal S. Solomon H. Chandarlapaty S. Levchenko A. Rosen N. Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis Mol. Cell 2021 81 708 723.e5 10.1016/j.molcel.2021.01.033 33606974 PMC8384339

44. Yang G. Murashige D.S. Humphrey S.J. James D.E. A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation Cell Rep. 2015 12 937 943 10.1016/j.celrep.2015.07.016 26235620

45. Sarbassov D.D. Guertin D.A. Ali S.M. Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex Science 2005 307 1098 1101 10.1126/science.1106148 15718470

46. Yang H. Jiang X. Li B. Yang H.J. Miller M. Yang A. Dhar A. Pavletich N.P. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40 Nature 2017 552 368 373 10.1038/nature25023 29236692 PMC5750076

47. Cormerais Y. Lapp S.C. Kalafut K.C. Cissé M.Y. Shin J. Stefadu B. Personnaz J. Schrötter S. Freed J. D’Amore A. AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth Dev. Cell 2025 60 2544 2557.e7 10.1016/j.devcel.2025.05.008 40480230 PMC12258181

48. Arif A. Jia J. Willard B. Li X. Fox P.L. Multisite Phosphorylation of S6K1 Directs a Kinase Phospho-code that Determines Substrate Selection Mol. Cell 2019 73 446 457.e6 10.1016/j.molcel.2018.11.017 30612880 PMC6415305

49. Bohm R. Imseng S. Jakob R.P. Hall M.N. Maier T. Hiller S. The dynamic mechanism of 4E-BP1 recognition and phosphorylation by mTORC1 Mol. Cell 2021 81 2403 2416.e5 10.1016/j.molcel.2021.03.031 33852892

50. Meyuhas O. Ribosomal Protein S6 Phosphorylation: Four Decades of Research Int. Rev. Cell Mol. Biol. 2015 320 41 73 10.1016/bs.ircmb.2015.07.006 26614871

51. Guo Y.J. Pan W.W. Liu S.B. Shen Z.F. Xu Y. Hu L.L. ERK/MAPK signalling pathway and tumorigenesis Exp. Ther. Med. 2020 19 1997 2007 10.3892/etm.2020.8454 32104259 PMC7027163

52. Kazemein Jasemi N.S. Herrmann C. Magdalena Estirado E. Gremer L. Willbold D. Brunsveld L. Dvorsky R. Ahmadian M.R. The intramolecular allostery of GRB2 governing its interaction with SOS1 is modulated by phosphotyrosine ligands Biochem. J. 2021 478 2793 2809 10.1042/BCJ20210105 34232285

53. Lavoie H. Gagnon J. Therrien M. ERK signalling: A master regulator of cell behaviour, life and fate Nat. Rev. Mol. Cell Biol. 2020 21 607 632 10.1038/s41580-020-0255-7 32576977

54. Stefanovsky V.Y. Pelletier G. Hannan R. Gagnon-Kugler T. Rothblum L.I. Moss T. An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF Mol. Cell 2001 8 1063 1073 10.1016/s1097-2765(01)00384-7 11741541

55. Zhao J. Yuan X. Frödin M. Grummt I. ERK-Dependent Phosphorylation of the Transcription Initiation Factor TIF-IA Is Required for RNA Polymerase I Transcription and Cell Growth Mol. Cell 2003 11 405 413 10.1016/S1097-2765(03)00036-4 12620228

56. Hadwiger J.A. Aranda R.G. Fatima S. Atypical MAP kinases—New insights and directions from amoeba J. Cell Sci. 2023 136 jcs261447 10.1242/jcs.261447 37850857 PMC10617611

57. Dahm K. Vijayarangakannan P. Wollscheid H.P. Schild H. Rajalingam K. Atypical MAPKs in cancer FEBS J. 2025 292 2173 2188 10.1111/febs.17283 39348153 PMC12062777

58. Elkhadragy L. Myers A. Long W. Role of the Atypical MAPK ERK3 in Cancer Growth and Progression Cancers 2024 16 1381 10.3390/cancers16071381 38611058 PMC11011113

59. Fernandez P.C. Frank S.R. Wang L. Schroeder M. Liu S. Greene J. Cocito A. Amati B. Genomic targets of the human c-Myc protein Genes Dev. 2003 17 1115 1129 10.1101/gad.1067003 12695333 PMC196049

60. Perna D. Fagà G. Verrecchia A. Gorski M.M. Barozzi I. Narang V. Khng J. Lim K.C. Sung W.K. Sanges R. Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts Oncogene 2012 31 1695 1709 10.1038/onc.2011.359 21860422 PMC3324106

61. Jha R.K. Kouzine F. Levens D. MYC function and regulation in physiological perspective Front. Cell Dev. Biol. 2023 11 1268275 10.3389/fcell.2023.1268275 37941901 PMC10627926

62. Jakobsen S.T. Siersbæk R. Transcriptional regulation by MYC: An emerging new model Oncogene 2025 44 1 7 10.1038/s41388-024-03174-2 39468222

63. Dhanasekaran R. Deutzmann A. Mahauad-Fernandez W.D. Hansen A.S. Gouw A.M. Felsher D.W. The MYC oncogene—The grand orchestrator of cancer growth and immune evasion Nat. Rev. Clin. Oncol. 2022 19 23 36 10.1038/s41571-021-00549-2 34508258 PMC9083341

64. Schaub F.X. Dhankani V. Berger A.C. Trivedi M. Richardson A.B. Shaw R. Zhao W. Zhang X. Ventura A. Liu Y. Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas Cell Syst. 2018 6 282 300.e282 10.1016/j.cels.2018.03.003 29596783 PMC5892207

65. van Riggelen J. Yetil A. Felsher D.W. MYC as a regulator of ribosome biogenesis and protein synthesis Nat. Rev. Cancer 2010 10 301 309 10.1038/nrc2819 20332779

66. Grandori C. Gomez-Roman N. Felton-Edkins Z.A. Ngouenet C. Galloway D.A. Eisenman R.N. White R.J. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I Nat. Cell Biol. 2005 7 311 318 10.1038/ncb1224 15723054

67. Arabi A. Wu S. Ridderstrale K. Bierhoff H. Shiue C. Fatyol K. Fahlen S. Hydbring P. Soderberg O. Grummt I. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription Nat. Cell Biol. 2005 7 303 310 10.1038/ncb1225 15723053

68. Brown I.N. Lafita-Navarro M.C. Conacci-Sorrell M. Regulation of Nucleolar Activity by MYC Cells 2022 11 574 10.3390/cells11030574 35159381 PMC8834138

69. Gomez-Roman N. Grandori C. Eisenman R.N. White R.J. Direct activation of RNA polymerase III transcription by c-Myc Nature 2003 421 290 294 10.1038/nature01327 12529648

70. Baluapuri A. Hofstetter J. Dudvarski Stankovic N. Endres T. Bhandare P. Vos S.M. Adhikari B. Schwarz J.D. Narain A. Vogt M. MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation Mol. Cell 2019 74 674 687.e11 10.1016/j.molcel.2019.02.031 30928206 PMC6527870

71. Scagnoli F. Palma A. Favia A. Scuoppo C. Illi B. Nasi S. A New Insight into MYC Action: Control of RNA Polymerase II Methylation and Transcription Termination Biomedicines 2023 11 412 10.3390/biomedicines11020412 36830948 PMC9952900

72. Mayer C. Zhao J. Yuan X. Grummt I. mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability Genes Dev. 2004 18 423 434 10.1101/gad.285504 15004009 PMC359396

73. Voit R. Grummt I. Phosphorylation of UBF at serine 388 is required for interaction with RNA polymerase I and activation of rDNA transcription Proc. Natl. Acad. Sci. USA 2001 98 13631 13636 10.1073/pnas.231071698 11698641 PMC61092

74. Voit R. Hoffmann M. Grummt I. Phosphorylation by G1-specific cdk-cyclin complexes activates the nucleolar transcription factor UBF EMBO J. 1999 18 1891 1899 10.1093/emboj/18.7.1891 10202152 PMC1171274

75. Klein J. Grummt I. Cell cycle-dependent regulation of RNA polymerase I transcription: The nucleolar transcription factor UBF is inactive in mitosis and early G1 Proc. Natl. Acad. Sci. USA 1999 96 6096 6101 10.1073/pnas.96.11.6096 10339547 PMC26841

76. Scheiblecker L. Kollmann K. Sexl V. CDK4/6 and MAPK-Crosstalk as Opportunity for Cancer Treatment Pharmaceuticals 2020 13 418 10.3390/ph13120418 33255177 PMC7760252

77. Potapova T.A. Unruh J.R. Conkright-Fincham J. Banks C.A.S. Florens L. Schneider D.A. Gerton J.L. Distinct states of nucleolar stress induced by anticancer drugs eLife 2023 12 RP88799 10.7554/eLife.88799 38099650 PMC10723795

78. Archambault V. Li J. Emond-Fraser V. Larouche M. Dephosphorylation in nuclear reassembly after mitosis Front. Cell Dev. Biol. 2022 10 1012768 10.3389/fcell.2022.1012768 36268509 PMC9576876

79. Holder J. Mohammed S. Barr F.A. Ordered dephosphorylation initiated by the selective proteolysis of cyclin B drives mitotic exit eLife 2020 9 e59885 10.7554/eLife.59885 32869743 PMC7529458

80. Lin C.H. Platt M.D. Ficarro S.B. Hoofnagle M.H. Shabanowitz J. Comai L. Hunt D.F. Owens G.K. Mass spectrometric identification of phosphorylation sites of rRNA transcription factor upstream binding factor Am. J. Physiol. Cell Physiol. 2007 292 C1617 C1624 10.1152/ajpcell.00176.2006 17182730

81. Heix J. Vente A. Voit R. Budde A. Michaelidis T.M. Grummt I. Mitotic silencing of human rRNA synthesis: Inactivation of the promoter selectivity factor SL1 by cdc2/cyclin B-mediated phosphorylation EMBO J. 1998 17 7373 7381 10.1093/emboj/17.24.7373 9857193 PMC1171082

82. Voit R. Seiler J. Grummt I. Cooperative Action of Cdk1/cyclin B and SIRT1 Is Required for Mitotic Repression of rRNA Synthesis PLoS Genet. 2015 11 e1005246 10.1371/journal.pgen.1005246 26023773 PMC4449194

83. Negi S.S. Olson M.O. Effects of interphase and mitotic phosphorylation on the mobility and location of nucleolar protein B23 J. Cell Sci. 2006 119 3676 3685 10.1242/jcs.03090 16912078

84. Westendorf J.M. Konstantinov K.N. Wormsley S. Shu M.D. Matsumoto-Taniura N. Pirollet F. Klier F.G. Gerace L. Baserga S.J. M phase phosphoprotein 10 is a human U3 small nucleolar ribonucleoprotein component Mol. Biol. Cell 1998 9 437 449 10.1091/mbc.9.2.437 9450966 PMC25272

85. Matsumoto-Taniura N. Pirollet F. Monroe R. Gerace L. Westendorf J.M. Identification of novel M phase phosphoproteins by expression cloning Mol. Biol. Cell 1996 7 1455 1469 10.1091/mbc.7.9.1455 8885239 PMC275994

86. Grummt I. Längst G. Epigenetic control of RNA polymerase I transcription in mammalian cells Biochim. Biophys. Acta (BBA)-Gene Regul. Mech. 2013 1829 393 404 10.1016/j.bbagrm.2012.10.004 23063748

87. Potapova T.A. Kostos P. McKinney S. Borchers M. Haug J. Guarracino A. Solar S.J. Mattingly M. Anez G.M. de Lima L.G. Chromosome-specific epigenetic control and transmission of ribosomal DNA arrays in Hominidae genomes Cell Genom. 2025 5 101031 10.1016/j.xgen.2025.101031 41043432 PMC12802695

88. Herdman C. Mars J.C. Stefanovsky V.Y. Tremblay M.G. Sabourin-Felix M. Lindsay H. Robinson M.D. Moss T. A unique enhancer boundary complex on the mouse ribosomal RNA genes persists after loss of Rrn3 or UBF and the inactivation of RNA polymerase I transcription PLoS Genet. 2017 13 e1006899 10.1371/journal.pgen.1006899 28715449 PMC5536353

89. Santoro R. Li J. Grummt I. The nucleolar remodeling complex NoRC mediates heterochromatin formation and silencing of ribosomal gene transcription Nat. Genet. 2002 32 393 396 10.1038/ng1010 12368916

90. Yang L. Song T. Chen L. Kabra N. Zheng H. Koomen J. Seto E. Chen J. Regulation of SirT1-nucleomethylin binding by rRNA coordinates ribosome biogenesis with nutrient availability Mol. Cell. Biol. 2013 33 3835 3848 10.1128/MCB.00476-13 23897426 PMC3811878

91. Murayama A. Ohmori K. Fujimura A. Minami H. Yasuzawa-Tanaka K. Kuroda T. Oie S. Daitoku H. Okuwaki M. Nagata K. Epigenetic control of rDNA loci in response to intracellular energy status Cell 2008 133 627 639 10.1016/j.cell.2008.03.030 18485871

92. Xie W. Ling T. Zhou Y. Feng W. Zhu Q. Stunnenberg H.G. Grummt I. Tao W. The chromatin remodeling complex NuRD establishes the poised state of rRNA genes characterized by bivalent histone modifications and altered nucleosome positions Proc. Natl. Acad. Sci. USA 2012 109 8161 8166 10.1073/pnas.1201262109 22570494 PMC3361413

93. Kobayashi T. Ribosomal RNA gene repeats, their stability and cellular senescence Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2014 90 119 129 10.2183/pjab.90.119 24727936 PMC4055705

94. Yang F. Guo X. Bao Y. Li R. The role of ribosomal DNA methylation in embryonic development, aging and diseases Epigenet. Chromatin 2024 17 23 10.1186/s13072-024-00548-4 39085958 PMC11290161

95. Pederson T. The plurifunctional nucleolus Nucleic Acids Res. 1998 26 3871 3876 10.1093/nar/26.17.3871 9705492 PMC147800

96. Andersen J.S. Lyon C.E. Fox A.H. Leung A.K. Lam Y.W. Steen H. Mann M. Lamond A.I. Directed proteomic analysis of the human nucleolus Curr. Biol. 2002 12 1 11 10.1016/s0960-9822(01)00650-9 11790298

97. Scherl A. Coute Y. Deon C. Calle A. Kindbeiter K. Sanchez J.C. Greco A. Hochstrasser D. Diaz J.J. Functional proteomic analysis of human nucleolus Mol. Biol. Cell 2002 13 4100 4109 10.1091/mbc.e02-05-0271 12429849 PMC133617

98. Andersen J.S. Lam Y.W. Leung A.K.L. Ong S.-E. Lyon C.E. Lamond A.I. Mann M. Nucleolar proteome dynamics Nature 2005 433 77 83 10.1038/nature03207 15635413

99. The Gene Ontology Consortium The Gene Ontology Resource: 20 years and still GOing strong Nucleic Acids Res. 2019 47 D330 D338 10.1093/nar/gky1055 30395331 PMC6323945

100. Coute Y. Burgess J.A. Diaz J.J. Chichester C. Lisacek F. Greco A. Sanchez J.C. Deciphering the human nucleolar proteome Mass Spectrom. Rev. 2006 25 215 234 10.1002/mas.20067 16211575

101. Tsai R.Y.L. Pederson T. Connecting the nucleolus to the cell cycle and human disease FASEB J. 2014 28 3290 3296 10.1096/fj.14-254680 24790035

102. Jarboui M.A. Wynne K. Elia G. Hall W.W. Gautier V.W. Proteomic profiling of the human T-cell nucleolus Mol. Immunol. 2011 49 441 452 10.1016/j.molimm.2011.09.005 22014684

103. Slomnicki L.P. Malinowska A. Kistowski M. Palusinski A. Zheng J.-J. Sepp M. Timmusk T. Dadlez M. Hetman M. Nucleolar Enrichment of Brain Proteins with Critical Roles in Human Neurodevelopment* Mol. Cell. Proteom. 2016 15 2055 2075 10.1074/mcp.M115.051920 27053602 PMC5083102

104. Ahmad Y. Boisvert F.M. Gregor P. Cobley A. Lamond A.I. NOPdb: Nucleolar Proteome Database—2008 update Nucleic Acids Res. 2009 37 D181 D184 10.1093/nar/gkn804 18984612 PMC2686505

105. Thul P.J. Åkesson L. Wiking M. Mahdessian D. Geladaki A. Ait Blal H. Alm T. Asplund A. Björk L. Breckels L.M. A subcellular map of the human proteome Science 2017 356 eaal3321 10.1126/science.aal3321 28495876

106. Li K. Xie X. Gao R. Chen Z. Yang M. Wen Z. Weng Y. Fan X. Zhang G. Liu L. Spatiotemporal protein interactome profiling through condensation-enhanced photocrosslinking Nat. Chem. 2025 17 111 123 10.1038/s41557-024-01663-1 39501047

107. Lee C. Quintana A. Suppanz I. Gomez-Auli A. Mittler G. Cissé I.I. Light-induced targeting enables proteomics on endogenous condensates Cell 2024 187 7079 7090.e17 10.1016/j.cell.2024.09.040 39426378 PMC11793346

108. Metge B.J. Elbahoty M.H. Elhamamsy A.R. Popple A.E. Papineni B. Samant R.S. Shevde L.A. Nucleolar proteomics identifies S100A16 as a key nucleolar protein driving breast cancer metastasis Cell Death Dis. 2025 16 638 10.1038/s41419-025-07963-9 40846689 PMC12373912

109. Gao J. Sun W. Chen Y. Liu T. Ge Z. Xu W. Lu Y. Wang W. Ma J. Ge H. Nucleolar beacon for monitoring nucleolar morphology and proteomics in living cells Sci. Adv. 2025 11 eadv7795 10.1126/sciadv.adv7795 40498842 PMC12154232

110. Iarovaia O.V. Ioudinkova E.S. Velichko A.K. Razin S.V. Manipulation of Cellular Processes via Nucleolus Hijaking in the Course of Viral Infection in Mammals Cells 2021 10 1597 10.3390/cells10071597 34202380 PMC8303250

111. Lee T.A. Han H. Polash A. Cho S.K. Lee J.W. Ra E.A. Lee E. Park A. Kang S. Choi J.L. The nucleolus is the site for inflammatory RNA decay during infection Nat. Commun. 2022 13 5203 10.1038/s41467-022-32856-2 36057640 PMC9440930

112. Sakthivel D. Brown-Suedel A. Bouchier-Hayes L. The role of the nucleolus in regulating the cell cycle and the DNA damage response Adv. Protein Chem. Struct. Biol. 2023 135 203 241 10.1016/bs.apcsb.2023.01.001 37061332

113. Pham A.T. Mani M. Wang X. Vafabakhsh R. Multiscale biophysical analysis of nucleolus disassembly during mitosis Proc. Natl. Acad. Sci. USA 2024 121 e2312250121 10.1073/pnas.2312250121 38285946 PMC10861868

114. Jellbauer S. Jansen R.-P. A putative function of the nucleolus in the assembly or maturation of specialized messenger ribonucleoprotein complexes RNA Biol. 2008 5 225 229 10.4161/rna.7163 19182521

115. Pontes O. Li C.F. Costa Nunes P. Haag J. Ream T. Vitins A. Jacobsen S.E. Pikaard C.S. The Arabidopsis chromatin-modifying nuclear siRNA pathway involves a nucleolar RNA processing center Cell 2006 126 79 92 10.1016/j.cell.2006.05.031 16839878

116. Feng S. Manley J.L. Beyond rRNA: Nucleolar transcription generates a complex network of RNAs with multiple roles in maintaining cellular homeostasis Genes Dev. 2022 36 876 886 10.1101/gad.349969.122 36207140 PMC9575697

117. Yuan F. Xu C. Li G. Tong T. Nucleolar TRF2 attenuated nucleolus stress-induced HCC cell-cycle arrest by altering rRNA synthesis Cell Death Dis. 2018 9 518 10.1038/s41419-018-0572-3 29725012 PMC5938709

118. Klump B.M. Perez G.I. Patrick E.M. Adams-Boone K. Cohen S.B. Han L. Yu K. Schmidt J.C. TCAB1 prevents nucleolar accumulation of the telomerase RNA to facilitate telomerase assembly Cell Rep. 2023 42 112577 10.1016/j.celrep.2023.112577 37267110 PMC10569210

119. Korsholm L.M. Gal Z. Nieto B. Quevedo O. Boukoura S. Lund C.C. Larsen D.H. Recent advances in the nucleolar responses to DNA double-strand breaks Nucleic Acids Res. 2020 48 9449 9461 10.1093/nar/gkaa713 32857853 PMC7515731

120. Xuan J. Gitareja K. Brajanovski N. Sanij E. Harnessing the Nucleolar DNA Damage Response in Cancer Therapy Genes 2021 12 1156 10.3390/genes12081156 34440328 PMC8393943

121. Boukoura S. Larsen D.H. Nucleolar organization and ribosomal DNA stability in response to DNA damage Curr. Opin. Cell Biol. 2024 89 102380 10.1016/j.ceb.2024.102380 38861757

122. Korsholm L.M. Gal Z. Lin L. Quevedo O. Ahmad D.A. Dulina E. Luo Y. Bartek J. Larsen D.H. Double-strand breaks in ribosomal RNA genes activate a distinct signaling and chromatin response to facilitate nucleolar restructuring and repair Nucleic Acids Res. 2019 47 8019 8035 10.1093/nar/gkz518 31184714 PMC6735822

123. Rubbi C.P. Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses EMBO J. 2003 22 6068 6077 10.1093/emboj/cdg579 14609953 PMC275437

124. Yang K. Yang J. Yi J. Nucleolar Stress: Hallmarks, sensing mechanism and diseases Cell Stress 2018 2 125 140 10.15698/cst2018.06.139 31225478 PMC6551681

125. Maehama T. Nishio M. Otani J. Mak T.W. Suzuki A. Nucleolar stress: Molecular mechanisms and related human diseases Cancer Sci. 2023 114 2078 2086 10.1111/cas.15755 36762786 PMC10154868

126. Boulon S. Westman B.J. Hutten S. Boisvert F.M. Lamond A.I. The nucleolus under stress Mol. Cell 2010 40 216 227 10.1016/j.molcel.2010.09.024 20965417 PMC2987465

127. Tchurikov N.A. Yudkin D.V. Gorbacheva M.A. Kulemzina A.I. Grischenko I.V. Fedoseeva D.M. Sosin D.V. Kravatsky Y.V. Kretova O.V. Hot spots of DNA double-strand breaks in human rDNA units are produced in vivo Sci. Rep. 2016 6 25866 10.1038/srep25866 27160357 PMC4861929

128. Shi T. van Soest D.M.K. Polderman P.E. Burgering B.M.T. Dansen T.B. DNA damage and oxidant stress activate p53 through differential upstream signaling pathways Free Radic. Biol. Med. 2021 172 298 311 10.1016/j.freeradbiomed.2021.06.013 34144191

129. Harding S.M. Boiarsky J.A. Greenberg R.A. ATM Dependent Silencing Links Nucleolar Chromatin Reorganization to DNA Damage Recognition Cell Rep. 2015 13 251 259 10.1016/j.celrep.2015.08.085 26440899 PMC4607662

130. Larsen D.H. Hari F. Clapperton J.A. Gwerder M. Gutsche K. Altmeyer M. Jungmichel S. Toledo L.I. Fink D. Rask M.-B. The NBS1–Treacle complex controls ribosomal RNA transcription in response to DNA damage Nat. Cell Biol. 2014 16 792 803 10.1038/ncb3007 25064736 PMC4962910

131. Mooser C. Symeonidou I.E. Leimbacher P.A. Ribeiro A. Shorrocks A.K. Jungmichel S. Larsen S.C. Knechtle K. Jasrotia A. Zurbriggen D. Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation Nat. Commun. 2020 11 123 10.1038/s41467-019-13981-x 31913317 PMC6949271

132. Ciccia A. Huang J.W. Izhar L. Sowa M.E. Harper J.W. Elledge S.J. Treacher Collins syndrome TCOF1 protein cooperates with NBS1 in the DNA damage response Proc. Natl. Acad. Sci. USA 2014 111 18631 18636 10.1073/pnas.1422488112 25512513 PMC4284564

133. Li J. Zhao H. McMahon A. Yan S. APE1 assembles biomolecular condensates to promote the ATR–Chk1 DNA damage response in nucleolus Nucleic Acids Res. 2022 50 10503 10525 10.1093/nar/gkac853 36200829 PMC9561277

134. Zhao H. Li J. You Z. Lindsay H.D. Yan S. Distinct regulation of ATM signaling by DNA single-strand breaks and APE1 Nat. Commun. 2024 15 6517 10.1038/s41467-024-50836-6 39112456 PMC11306256

135. Zhao H. Richardson C. Marriott I. Yang I.H. Yan S. APE1 is a master regulator of the ATR-/ATM-mediated DNA damage response DNA Repair 2024 144 103776 10.1016/j.dnarep.2024.103776 39461278 PMC11611674

136. Sakai D. Dixon J. Achilleos A. Dixon M. Trainor P.A. Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation Nat. Commun. 2016 7 10328 10.1038/ncomms10328 26792133 PMC4735750

137. Jones N.C. Lynn M.L. Gaudenz K. Sakai D. Aoto K. Rey J.P. Glynn E.F. Ellington L. Du C. Dixon J. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function Nat. Med. 2008 14 125 133 10.1038/nm1725 18246078 PMC3093709

138. Mah L.J. El-Osta A. Karagiannis T.C. γH2AX: A sensitive molecular marker of DNA damage and repair Leukemia 2010 24 679 686 10.1038/leu.2010.6 20130602

139. Calo E. Gu B. Bowen M.E. Aryan F. Zalc A. Liang J. Flynn R.A. Swigut T. Chang H.Y. Attardi L.D. Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders Nature 2018 554 112 117 10.1038/nature25449 29364875 PMC5927778

140. Guetg C. Scheifele F. Rosenthal F. Hottiger M.O. Santoro R. Inheritance of silent rDNA chromatin is mediated by PARP1 via noncoding RNA Mol. Cell 2012 45 790 800 10.1016/j.molcel.2012.01.024 22405650

141. Kołacz K. Robaszkiewicz A. PARP1 at the crossroad of cellular senescence and nucleolar processes Ageing Res. Rev. 2024 94 102206 10.1016/j.arr.2024.102206 38278370

142. Veith S. Schink A. Engbrecht M. Mack M. Rank L. Rossatti P. Hakobyan M. Goly D. Hefele T. Frensch M. PARP1 regulates DNA damage-induced nucleolar-nucleoplasmic shuttling of WRN and XRCC1 in a toxicant and protein-specific manner Sci. Rep. 2019 9 10075 10.1038/s41598-019-46358-7 31296950 PMC6624289

143. Zhu M. Wu W. Togashi Y. Liang W. Miyoshi Y. Ohta T. HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN Sci. Rep. 2021 11 360 10.1038/s41598-020-79715-y 33432007 PMC7801386

144. Shiratori M. Suzuki T. Itoh C. Goto M. Furuichi Y. Matsumoto T. WRN helicase accelerates the transcription of ribosomal RNA as a component of an RNA polymerase I-associated complex Oncogene 2002 21 2447 2454 10.1038/sj.onc.1205334 11971179

145. Grierson P.M. Lillard K. Behbehani G.K. Combs K.A. Bhattacharyya S. Acharya S. Groden J. BLM helicase facilitates RNA polymerase I-mediated ribosomal RNA transcription Hum. Mol. Genet. 2012 21 1172 1183 10.1093/hmg/ddr545 22106380 PMC3277314

146. Bursac S. Brdovcak M.C. Pfannkuchen M. Orsolic I. Golomb L. Zhu Y. Katz C. Daftuar L. Grabusic K. Vukelic I. Mutual protection of ribosomal proteins L5 and L11 from degradation is essential for p53 activation upon ribosomal biogenesis stress Proc. Natl. Acad. Sci. USA 2012 109 20467 20472 10.1073/pnas.1218535109 23169665 PMC3528581

147. Shi D. Gu W. Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity Genes Cancer 2012 3 240 248 10.1177/1947601912455199 23150757 PMC3494363

148. Donati G. Peddigari S. Mercer C.A. Thomas G. 5S ribosomal RNA is an essential component of a nascent ribosomal precursor complex that regulates the Hdm2-p53 checkpoint Cell Rep. 2013 4 87 98 10.1016/j.celrep.2013.05.045 23831031 PMC3928573

149. Fumagalli S. Ivanenkov V.V. Teng T. Thomas G. Suprainduction of p53 by disruption of 40S and 60S ribosome biogenesis leads to the activation of a novel G2/M checkpoint Genes Dev. 2012 26 1028 1040 10.1101/gad.189951.112 22588717 PMC3360559

150. Fischer M. Census and evaluation of p53 target genes Oncogene 2017 36 3943 3956 10.1038/onc.2016.502 28288132 PMC5511239

151. Xiong X. Zhao Y. He H. Sun Y. Ribosomal protein S27-like and S27 interplay with p53-MDM2 axis as a target, a substrate and a regulator Oncogene 2011 30 1798 1811 10.1038/onc.2010.569 21170087 PMC3077453

152. Xiong X. Zhao Y. Tang F. Wei D. Thomas D. Wang X. Liu Y. Zheng P. Sun Y. Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis eLife 2014 3 e02236 10.7554/eLife.02236 25144937 PMC4163686

153. Sun X.X. DeVine T. Challagundla K.B. Dai M.S. Interplay between ribosomal protein S27a and MDM2 protein in p53 activation in response to ribosomal stress J. Biol. Chem. 2011 286 22730 22741 10.1074/jbc.M111.223651 21561866 PMC3123040

154. Cui D. Li L. Lou H. Sun H. Ngai S.M. Shao G. Tang J. The ribosomal protein S26 regulates p53 activity in response to DNA damage Oncogene 2014 33 2225 2235 10.1038/onc.2013.170 23728348

155. Zhang X. Wang W. Wang H. Wang M.H. Xu W. Zhang R. Identification of ribosomal protein S25 (RPS25)-MDM2-p53 regulatory feedback loop Oncogene 2013 32 2782 2791 10.1038/onc.2012.289 22777350 PMC6714567

156. Wei S. Chen X. McGraw K. Zhang L. Komrokji R. Clark J. Caceres G. Billingsley D. Sokol L. Lancet J. Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion Oncogene 2013 32 1110 1120 10.1038/onc.2012.139 22525275 PMC3751397

157. Zhou X. Hao Q. Liao J. Zhang Q. Lu H. Ribosomal protein S14 unties the MDM2-p53 loop upon ribosomal stress Oncogene 2013 32 388 396 10.1038/onc.2012.63 22391559 PMC3736832

158. Chen D. Zhang Z. Li M. Wang W. Li Y. Rayburn E.R. Hill D.L. Wang H. Zhang R. Ribosomal protein S7 as a novel modulator of p53-MDM2 interaction: Binding to MDM2, stabilization of p53 protein, and activation of p53 function Oncogene 2007 26 5029 5037 10.1038/sj.onc.1210327 17310983

159. Yadavilli S. Mayo L.D. Higgins M. Lain S. Hegde V. Deutsch W.A. Ribosomal protein S3: A multi-functional protein that interacts with both p53 and MDM2 through its KH domain DNA Repair 2009 8 1215 1224 10.1016/j.dnarep.2009.07.003 19656744 PMC2748156

160. Daftuar L. Zhu Y. Jacq X. Prives C. Ribosomal proteins RPL37, RPS15 and RPS20 regulate the Mdm2-p53-MdmX network PLoS ONE 2013 8 e68667 10.1371/journal.pone.0068667 23874713 PMC3713000

161. Zhang Y. Wang J. Yuan Y. Zhang W. Guan W. Wu Z. Jin C. Chen H. Zhang L. Yang X. Negative regulation of HDM2 to attenuate p53 degradation by ribosomal protein L26 Nucleic Acids Res. 2010 38 6544 6554 10.1093/nar/gkq536 20542919 PMC2965247

162. Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition Mol. Cell. Biol. 2004 24 7654 7668 10.1128/MCB.24.17.7654-7668.2004 15314173 PMC506971

163. Cao B. Fang Z. Liao P. Zhou X. Xiong J. Zeng S. Lu H. Cancer-mutated ribosome protein L22 (RPL22/eL22) suppresses cancer cell survival by blocking p53-MDM2 circuit Oncotarget 2017 8 90651 90661 10.18632/oncotarget.21544 29207594 PMC5710875

164. Lohrum M.A. Ludwig R.L. Kubbutat M.H. Hanlon M. Vousden K.H. Regulation of HDM2 activity by the ribosomal protein L11 Cancer Cell 2003 3 577 587 10.1016/s1535-6108(03)00134-x 12842086

165. Bai D. Zhang J. Xiao W. Zheng X. Regulation of the HDM2-p53 pathway by ribosomal protein L6 in response to ribosomal stress Nucleic Acids Res. 2014 42 1799 1811 10.1093/nar/gkt971 24174547 PMC3919599

166. Li M. Gu W. A Critical Role for Noncoding 5S rRNA in Regulating Mdmx Stability Mol. Cell 2011 43 1023 1032 10.1016/j.molcel.2011.08.020 21925390 PMC3627499

167. He H. Sun Y. Ribosomal protein S27L is a direct p53 target that regulates apoptosis Oncogene 2007 26 2707 2716 10.1038/sj.onc.1210073 17057733

168. Zhu Y. Poyurovsky M.V. Li Y. Biderman L. Stahl J. Jacq X. Prives C. Ribosomal protein S7 is both a regulator and a substrate of MDM2 Mol. Cell 2009 35 316 326 10.1016/j.molcel.2009.07.014 19683495 PMC2896961

169. Ofir-Rosenfeld Y. Boggs K. Michael D. Kastan M.B. Oren M. Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26 Mol. Cell 2008 32 180 189 10.1016/j.molcel.2008.08.031 18951086 PMC2587494

170. Miyao S. Saito K. Oshima R. Kawahara K. Nagahama M. MTR4 adaptor PICT1 functions in two distinct steps during pre-rRNA processing Biochem. Biophys. Res. Commun. 2022 637 203 209 10.1016/j.bbrc.2022.11.018 36403484

171. Yim J.H. Kim Y.J. Ko J.H. Cho Y.E. Kim S.M. Kim J.Y. Lee S. Park J.H. The putative tumor suppressor gene GLTSCR2 induces PTEN-modulated cell death Cell Death Differ. 2007 14 1872 1879 10.1038/sj.cdd.4402204 17657248

172. Sasaki M. Kawahara K. Nishio M. Mimori K. Kogo R. Hamada K. Itoh B. Wang J. Komatsu Y. Yang Y.R. Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11 Nat. Med. 2011 17 944 951 10.1038/nm.2392 21804542 PMC4578312

173. Uchi R. Kogo R. Kawahara K. Sudo T. Yokobori T. Eguchi H. Sugimachi K. Maehama T. Mori M. Suzuki A. PICT1 regulates TP53 via RPL11 and is involved in gastric cancer progression Br. J. Cancer 2013 109 2199 2206 10.1038/bjc.2013.561 24045667 PMC3798961

174. Chen H. Han L. Tsai H. Wang Z. Wu Y. Duo Y. Cao W. Chen L. Tan Z. Xu N. PICT-1 is a key nucleolar sensor in DNA damage response signaling that regulates apoptosis through the RPL11-MDM2-p53 pathway Oncotarget 2016 7 83241 83257 10.18632/oncotarget.13082 27829214 PMC5347766

175. Lee S. Kim J.Y. Kim Y.J. Seok K.O. Kim J.H. Chang Y.J. Kang H.Y. Park J.H. Nucleolar protein GLTSCR2 stabilizes p53 in response to ribosomal stresses Cell Death Differ. 2012 19 1613 1622 10.1038/cdd.2012.40 22522597 PMC3438492

176. Wu Y. Wu X. Li Y. Zhao W. Yue Y. Wu B. Liu J. Chen X. Shen A. Comprehensive Analysis of Glutamate-Rich WD Repeat-Containing Protein 1 and Its Potential Clinical Significance for Pancancer Biomed. Res. Int. 2021 2021 8201377 10.1155/2021/8201377 34616846 PMC8490071

177. Wang Q. Ren H. Xu Y. Jiang J. Wudu M. Liu Z. Su H. Jiang X. Zhang Y. Zhang B. GRWD1 promotes cell proliferation and migration in non-small cell lung cancer by activating the Notch pathway Exp. Cell Res. 2020 387 111806 10.1016/j.yexcr.2019.111806 31891681

178. Zhou X. Shang J. Liu X. Zhuang J.F. Yang Y.F. Zhang Y.Y. Guan G.X. Clinical Significance and Oncogenic Activity of GRWD1 Overexpression in the Development of Colon Carcinoma Onco Targets Ther. 2021 14 1565 1580 10.2147/OTT.S290475 33688204 PMC7936717

179. Kayama K. Watanabe S. Takafuji T. Tsuji T. Hironaka K. Matsumoto M. Nakayama K.I. Enari M. Kohno T. Shiraishi K. GRWD1 negatively regulates p53 via the RPL11-MDM2 pathway and promotes tumorigenesis EMBO Rep. 2017 18 123 137 10.15252/embr.201642444 27856536 PMC5210153

180. Ichikawa M.K. Saitoh M. Direct and indirect roles of GRWD1 in the inactivation of p53 in cancer J. Biochem. 2022 171 601 603 10.1093/jb/mvac010 35171268

181. Fujiyama H. Tsuji T. Hironaka K. Yoshida K. Sugimoto N. Fujita M. GRWD1 directly interacts with p53 and negatively regulates p53 transcriptional activity J. Biochem. 2020 167 15 24 10.1093/jb/mvz075 31545368

182. Mahata B. Sundqvist A. Xirodimas D.P. Recruitment of RPL11 at promoter sites of p53-regulated genes upon nucleolar stress through NEDD8 and in an Mdm2-dependent manner Oncogene 2012 31 3060 3071 10.1038/onc.2011.482 22081073

183. Kuroda T. Murayama A. Katagiri N. Ohta Y.M. Fujita E. Masumoto H. Ema M. Takahashi S. Kimura K. Yanagisawa J. RNA content in the nucleolus alters p53 acetylation via MYBBP1A EMBO J. 2011 30 1054 1066 10.1038/emboj.2011.23 21297583 PMC3061030

184. Yamauchi T. Keough R.A. Gonda T.J. Ishii S. Ribosomal stress induces processing of Mybbp1a and its translocation from the nucleolus to the nucleoplasm Genes Cells 2008 13 27 39 10.1111/j.1365-2443.2007.01148.x 18173745

185. Takagi M. Absalon M.J. McLure K.G. Kastan M.B. Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin Cell 2005 123 49 63 10.1016/j.cell.2005.07.034 16213212

186. Gibbs E. Miao Q. Ferrolino M. Bajpai R. Hassan A. Phillips A.H. Pitre A. Kümmerle R. Miller S. Nagy G. p14ARF forms meso-scale assemblies upon phase separation with NPM1 Nat. Commun. 2024 15 9531 10.1038/s41467-024-53904-z 39528457 PMC11555371

187. Kowalczyk D. Nakasone M.A. Smith B.O. Huang D.T. Bivalent binding of p14ARF to MDM2 RING and acidic domains inhibits E3 ligase function Life Sci. Alliance 2022 5 e202201472 10.26508/lsa.202201472 35944929 PMC9366199

188. Kunchala P. Kuravi S. Jensen R. McGuirk J. Balusu R. When the good go bad: Mutant NPM1 in acute myeloid leukemia Blood Rev. 2018 32 167 183 10.1016/j.blre.2017.11.001 29157973

189. Fukawa T. Ono M. Matsuo T. Uehara H. Miki T. Nakamura Y. Kanayama H.O. Katagiri T. DDX31 regulates the p53-HDM2 pathway and rRNA gene transcription through its interaction with NPM1 in renal cell carcinomas Cancer Res. 2012 72 5867 5877 10.1158/0008-5472.CAN-12-1645 23019224

190. Stott F.J. Bates S. James M.C. McConnell B.B. Starborg M. Brookes S. Palmero I. Ryan K. Hara E. Vousden K.H. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2 EMBO J. 1998 17 5001 5014 10.1093/emboj/17.17.5001 9724636 PMC1170828

191. Fregoso O.I. Das S. Akerman M. Krainer A.R. Splicing-factor oncoprotein SRSF1 stabilizes p53 via RPL5 and induces cellular senescence Mol. Cell 2013 50 56 66 10.1016/j.molcel.2013.02.001 23478443 PMC3628402

192. Yu W. Qiu Z. Gao N. Wang L. Cui H. Qian Y. Jiang L. Luo J. Yi Z. Lu H. PAK1IP1, a ribosomal stress-induced nucleolar protein, regulates cell proliferation via the p53-MDM2 loop Nucleic Acids Res. 2011 39 2234 2248 10.1093/nar/gkq1117 21097889 PMC3064775

193. Xie N. Ma L. Zhu F. Zhao W. Tian F. Yuan F. Fu J. Huang D. Lv C. Tong T. Regulation of the MDM2-p53 pathway by the nucleolar protein CSIG in response to nucleolar stress Sci. Rep. 2016 6 36171 10.1038/srep36171 27811966 PMC5095888

194. Dai M.S. Sun X.X. Lu H. Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2 Mol. Cell. Biol. 2008 28 4365 4376 10.1128/MCB.01662-07 18426907 PMC2447154

195. Yu X. Cao J. Wang B. Fu J. Liu J. Sui T. Wang Z. Wu C. Chang J. Cao X. Silencing PIM1 inhibits ENO1-induced AKT activation and attenuates fibrillogenesis during spinal cord injury-induced skeletal muscle atrophy J. Biol. Chem. 2025 301 110398 10.1016/j.jbc.2025.110398 40543593 PMC12305723

196. Sagar V. Caldarola S. Aria V. Monteleone V. Fuoco C. Gargioli C. Cannata S. Loreni F. PIM1 destabilization activates a p53-dependent response to ribosomal stress in cancer cells Oncotarget 2016 7 23837 23849 10.18632/oncotarget.8070 26993775 PMC5029667

197. Iadevaia V. Caldarola S. Biondini L. Gismondi A. Karlsson S. Dianzani I. Loreni F. PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression Oncogene 2010 29 5490 5499 10.1038/onc.2010.279 20639905

198. Chen J. Guo K. Kastan M.B. Interactions of nucleolin and ribosomal protein L26 (RPL26) in translational control of human p53 mRNA J. Biol. Chem. 2012 287 16467 16476 10.1074/jbc.M112.349274 22433872 PMC3351294

199. Daniely Y. Dimitrova D.D. Borowiec J.A. Stress-dependent nucleolin mobilization mediated by p53-nucleolin complex formation Mol. Cell. Biol. 2002 22 6014 6022 10.1128/MCB.22.16.6014-6022.2002 12138209 PMC133981

200. Kim H.D. Kim T.S. Kim J. Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest Oncogene 2011 30 3317 3327 10.1038/onc.2011.47 21383696

201. Donati G. Brighenti E. Vici M. Mazzini G. Trere D. Montanaro L. Derenzini M. Selective inhibition of rRNA transcription downregulates E2F-1: A new p53-independent mechanism linking cell growth to cell proliferation J. Cell Sci. 2011 124 3017 3028 10.1242/jcs.086074 21878508

202. Pecoraro A. Carotenuto P. Russo G. Russo A. Ribosomal protein uL3 targets E2F1 and Cyclin D1 in cancer cell response to nucleolar stress Sci. Rep. 2019 9 15431 10.1038/s41598-019-51723-7 31659203 PMC6817900

203. Sunada S. Saito H. Zhang D. Xu Z. Miki Y. CDK1 inhibitor controls G2/M phase transition and reverses DNA damage sensitivity Biochem. Biophys. Res. Commun. 2021 550 56 61 10.1016/j.bbrc.2021.02.117 33684621

204. Pecoraro A. Carotenuto P. Franco B. De Cegli R. Russo G. Russo A. Role of uL3 in the Crosstalk between Nucleolar Stress and Autophagy in Colon Cancer Cells Int. J. Mol. Sci. 2020 21 2143 10.3390/ijms21062143 32244996 PMC7139652

205. Russo A. Maiolino S. Pagliara V. Ungaro F. Tatangelo F. Leone A. Scalia G. Budillon A. Quaglia F. Russo G. Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles Oncotarget 2016 7 79670 79687 10.18632/oncotarget.13216 27835895 PMC5346744

206. Lee S.B. Kwon I.S. Park J. Lee K.H. Ahn Y. Lee C. Kim J. Choi S.Y. Cho S.W. Ahn J.Y. Ribosomal protein S3, a new substrate of Akt, serves as a signal mediator between neuronal apoptosis and DNA repair J. Biol. Chem. 2010 285 29457 29468 10.1074/jbc.M110.131367 20605787 PMC2937978

207. Russo A. Esposito D. Catillo M. Pietropaolo C. Crescenzi E. Russo G. Human rpL3 induces G 1 /S arrest or apoptosis by modulating p21waf1/cip1 levels in a p53-independent manner Cell Cycle 2013 12 76 87 10.4161/cc.22963 23255119 PMC3570520

208. Russo A. Pagliara V. Albano F. Esposito D. Sagar V. Loreni F. Irace C. Santamaria R. Russo G. Regulatory role of rpL3 in cell response to nucleolar stress induced by Act D in tumor cells lacking functional p53 Cell Cycle 2016 15 41 51 10.1080/15384101.2015.1120926 26636733 PMC4825706

209. Pagliara V. Saide A. Mitidieri E. d’Emmanuele di Villa Bianca R. Sorrentino R. Russo G. Russo A. 5-FU targets rpL3 to induce mitochondrial apoptosis via cystathionine-beta-synthase in colon cancer cells lacking p53 Oncotarget 2016 7 50333 50348 10.18632/oncotarget.10385 27385096 PMC5226586

210. Thoms H.C. Stark L.A. The NF-kappaB Nucleolar Stress Response Pathway Biomedicines 2021 9 1082 10.3390/biomedicines9091082 34572268 PMC8471347

211. Chen J. Lobb I.T. Morin P. Novo S.M. Simpson J. Kennerknecht K. von Kriegsheim A. Batchelor E.E. Oakley F. Stark L.A. Identification of a novel TIF-IA-NF-kappaB nucleolar stress response pathway Nucleic Acids Res. 2018 46 6188 6205 10.1093/nar/gky455 29873780 PMC6158704

212. Russo A. Saide A. Cagliani R. Cantile M. Botti G. Russo G. rpL3 promotes the apoptosis of p53 mutated lung cancer cells by down-regulating CBS and NFκB upon 5-FU treatment Sci. Rep. 2016 6 38369 10.1038/srep38369 27924828 PMC5141482

213. Yang H.J. Youn H. Seong K.M. Jin Y.W. Kim J. Youn B. Phosphorylation of ribosomal protein S3 and antiapoptotic TRAF2 protein mediates radioresistance in non-small cell lung cancer cells J. Biol. Chem. 2013 288 2965 2975 10.1074/jbc.M112.385989 23188828 PMC3561521

214. Challagundla K.B. Sun X.X. Zhang X. DeVine T. Zhang Q. Sears R.C. Dai M.S. Ribosomal protein L11 recruits miR-24/miRISC to repress c-Myc expression in response to ribosomal stress Mol. Cell. Biol. 2011 31 4007 4021 10.1128/MCB.05810-11 21807902 PMC3187350

215. Zhou X. Hao Q. Liao J.M. Liao P. Lu H. Ribosomal protein S14 negatively regulates c-Myc activity J. Biol. Chem. 2013 288 21793 21801 10.1074/jbc.M112.445122 23775087 PMC3724636

216. Liao J.M. Zhou X. Gatignol A. Lu H. Ribosomal proteins L5 and L11 co-operatively inactivate c-Myc via RNA-induced silencing complex Oncogene 2014 33 4916 4923 10.1038/onc.2013.430 24141778 PMC4026346

217. Lo S.J. Fan L.C. Tsai Y.F. Lin K.Y. Huang H.L. Wang T.H. Liu H. Chen T.C. Huang S.F. Chang C.J. A novel interaction of nucleophosmin with BCL2-associated X protein regulating death evasion and drug sensitivity in human hepatoma cells Hepatology 2013 57 1893 1905 10.1002/hep.26209 23258611

218. Pfister A.S. Keil M. Kuhl M. The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway J. Biol. Chem. 2015 290 10905 10918 10.1074/jbc.M114.634246 25759387 PMC4409253

219. Hein N. Cameron D.P. Hannan K.M. Nguyen N.N. Fong C.Y. Sornkom J. Wall M. Pavy M. Cullinane C. Diesch J. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population Blood 2017 129 2882 2895 10.1182/blood-2016-05-718171 28283481 PMC5445570

220. Eymin B. Claverie P. Salon C. Leduc C. Col E. Brambilla E. Khochbin S. Gazzeri S. p14ARF activates a Tip60-dependent and p53-independent ATM/ATR/CHK pathway in response to genotoxic stress Mol. Cell. Biol. 2006 26 4339 4350 10.1128/MCB.02240-05 16705183 PMC1489086

221. Zhou X. Hao Q. Zhang Q. Liao J.M. Ke J.W. Liao P. Cao B. Lu H. Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition Cell Death Differ. 2015 22 755 766 10.1038/cdd.2014.167 25301064 PMC4392073

222. Menjivar-Vallecillo M.J. Padilla-Claros N.V. Gavarrete-Garrido P. Leon-Castaneda S.A. Ramos-Zaldivar H.M. The Nucleolus and Its Associated Pathologies WIREs Mech. Dis. 2025 17 e70003 10.1002/wsbm.70003 40916191

223. Derenzini M. Montanaro L. Trere D. What the nucleolus says to a tumour pathologist Histopathology 2009 54 753 762 10.1111/j.1365-2559.2008.03168.x 19178588

224. Derenzini M. Trere D. Pession A. Govoni M. Sirri V. Chieco P. Nucleolar size indicates the rapidity of cell proliferation in cancer tissues J. Pathol. 2000 191 181 186 10.1002/(SICI)1096-9896(200006)191:2<181::AID-PATH607>3.0.CO;2-V 10861579

225. Drygin D. Rice W.G. Grummt I. The RNA polymerase I transcription machinery: An emerging target for the treatment of cancer Annu. Rev. Pharmacol. Toxicol. 2010 50 131 156 10.1146/annurev.pharmtox.010909.105844 20055700

226. Barna M. Pusic A. Zollo O. Costa M. Kondrashov N. Rego E. Rao P.H. Ruggero D. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency Nature 2008 456 971 975 10.1038/nature07449 19011615 PMC2880952

227. Bywater M.J. Poortinga G. Sanij E. Hein N. Peck A. Cullinane C. Wall M. Cluse L. Drygin D. Anderes K. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53 Cancer Cell 2012 22 51 65 10.1016/j.ccr.2012.05.019 22789538 PMC3749732

228. Hwang S.P. Denicourt C. The impact of ribosome biogenesis in cancer: From proliferation to metastasis NAR Cancer 2024 6 zcae017 10.1093/narcan/zcae017 38633862 PMC11023387

229. Hanahan D. Weinberg R.A. Hallmarks of Cancer: The Next Generation Cell 2011 144 646 674 10.1016/j.cell.2011.02.013 21376230

230. Papa A. Pandolfi P.P. The PTEN(-)PI3K Axis in Cancer Biomolecules 2019 9 153 10.3390/biom9040153 30999672 PMC6523724

231. Mandigo A.C. Tomlins S.A. Kelly W.K. Knudsen K.E. Relevance of pRB Loss in Human Malignancies Clin. Cancer Res. 2022 28 255 264 10.1158/1078-0432.CCR-21-1565 34407969 PMC9306333

232. Liu Y. Su Z. Tavana O. Gu W. Understanding the complexity of p53 in a new era of tumor suppression Cancer Cell 2024 42 946 967 10.1016/j.ccell.2024.04.009 38729160 PMC11190820

233. Bahar M.E. Kim H.J. Kim D.R. Targeting the RAS/RAF/MAPK pathway for cancer therapy: From mechanism to clinical studies Signal Transduct. Target. Ther. 2023 8 455 10.1038/s41392-023-01705-z 38105263 PMC10725898

234. Diesch J. Bywater M.J. Sanij E. Cameron D.P. Schierding W. Brajanovski N. Son J. Sornkom J. Hein N. Evers M. Changes in long-range rDNA-genomic interactions associate with altered RNA polymerase II gene programs during malignant transformation Commun. Biol. 2019 2 39 10.1038/s42003-019-0284-y 30701204 PMC6349880

235. Zhang S. Yu D. PI(3)king apart PTEN’s role in cancer Clin. Cancer Res. 2010 16 4325 4330 10.1158/1078-0432.CCR-09-2990 20622047

236. Yuan T.L. Cantley L.C. PI3K pathway alterations in cancer: Variations on a theme Oncogene 2008 27 5497 5510 10.1038/onc.2008.245 18794884 PMC3398461

237. Osborne J.K. Zaganjor E. Cobb M.H. Signal control through Raf: In sickness and in health Cell Res. 2012 22 14 22 10.1038/cr.2011.193 22143568 PMC3351917

238. Pylayeva-Gupta Y. Grabocka E. Bar-Sagi D. RAS oncogenes: Weaving a tumorigenic web Nat. Rev. Cancer 2011 11 761 774 10.1038/nrc3106 21993244 PMC3632399

239. Destefanis F. Manara V. Bellosta P. Myc as a Regulator of Ribosome Biogenesis and Cell Competition: A Link to Cancer Int. J. Mol. Sci. 2020 21 4037 10.3390/ijms21114037 32516899 PMC7312820

240. Ebright R.Y. Lee S. Wittner B.S. Niederhoffer K.L. Nicholson B.T. Bardia A. Truesdell S. Wiley D.F. Wesley B. Li S. Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis Science 2020 367 1468 1473 10.1126/science.aay0939 32029688 PMC7307008

241. Yong W.H. Shabihkhani M. Telesca D. Yang S. Tso J.L. Menjivar J.C. Wei B. Lucey G.M. Mareninov S. Chen Z. Ribosomal Proteins RPS11 and RPS20, Two Stress-Response Markers of Glioblastoma Stem Cells, Are Novel Predictors of Poor Prognosis in Glioblastoma Patients PLoS ONE 2015 10 e0141334 10.1371/journal.pone.0141334 26506620 PMC4624638

242. Artero-Castro A. Castellvi J. Garcia A. Hernandez J. Ramon y Cajal S. Lleonart M.E. Expression of the ribosomal proteins Rplp0, Rplp1, and Rplp2 in gynecologic tumors Hum. Pathol. 2011 42 194 203 10.1016/j.humpath.2010.04.020 21040949

243. Fancello L. Kampen K.R. Hofman I.J. Verbeeck J. De Keersmaecker K. The ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in multiple cancer types Oncotarget 2017 8 14462 14478 10.18632/oncotarget.14895 28147343 PMC5362418

244. Nieminen T.T. O’Donohue M.F. Wu Y. Lohi H. Scherer S.W. Paterson A.D. Ellonen P. Abdel-Rahman W.M. Valo S. Mecklin J.P. Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency Gastroenterology 2014 147 595 598.e5 10.1053/j.gastro.2014.06.009 24941021 PMC4155505

245. Vlachos A. Acquired ribosomopathies in leukemia and solid tumors Hematol. Am. Soc. Hematol. Educ. Program 2017 2017 716 719 10.1182/asheducation-2017.1.716 29222326 PMC6142526

246. Yu L. Kim H.T. Kasar S. Benien P. Du W. Hoang K. Aw A. Tesar B. Improgo R. Fernandes S. Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation Clin. Cancer Res. 2017 23 735 745 10.1158/1078-0432.CCR-16-0594 27503198 PMC5467311

247. Oršolić I. Bursać S. Jurada D. Drmić Hofman I. Dembić Z. Bartek J. Mihalek I. Volarević S. Cancer-associated mutations in the ribosomal protein L5 gene dysregulate the HDM2/p53-mediated ribosome biogenesis checkpoint Oncogene 2020 39 3443 3457 10.1038/s41388-020-1231-6 32108164

248. Ferreira A.M. Tuominen I. van Dijk-Bos K. Sanjabi B. van der Sluis T. van der Zee A.G. Hollema H. Zazula M. Sijmons R.H. Aaltonen L.A. High frequency of RPL22 mutations in microsatellite-unstable colorectal and endometrial tumors Hum. Mutat. 2014 35 1442 1445 10.1002/humu.22686 25196364

249. El Khoury W. Nasr Z. Deregulation of ribosomal proteins in human cancers Biosci. Rep. 2021 41 BSR20211577 10.1042/BSR20211577 34873618 PMC8685657

250. Kang J. Brajanovski N. Chan K.T. Xuan J. Pearson R.B. Sanij E. Ribosomal proteins and human diseases: Molecular mechanisms and targeted therapy Signal Transduct. Target. Ther. 2021 6 323 10.1038/s41392-021-00728-8 34462428 PMC8405630

251. Dai M.S. Sears R. Lu H. Feedback regulation of c-Myc by ribosomal protein L11 Cell Cycle 2007 6 2735 2741 10.4161/cc.6.22.4895 18032916 PMC2694724

252. Morgado-Palacin L. Varetti G. Llanos S. Gomez-Lopez G. Martinez D. Serrano M. Partial Loss of Rpl11 in Adult Mice Recapitulates Diamond-Blackfan Anemia and Promotes Lymphomagenesis Cell Rep. 2015 13 712 722 10.1016/j.celrep.2015.09.038 26489471

253. Lior C. Barki D. Halperin C. Iacobuzio-Donahue C.A. Kelsen D. Shouval R.S. Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response Cell Rep. 2024 43 114236 10.1016/j.celrep.2024.114236 38758650 PMC11156623

254. Chen X. Zhang T. Su W. Dou Z. Zhao D. Jin X. Lei H. Wang J. Xie X. Cheng B. Mutant p53 in cancer: From molecular mechanism to therapeutic modulation Cell Death Dis. 2022 13 974 10.1038/s41419-022-05408-1 36400749 PMC9674619

255. Ajore R. Raiser D. McConkey M. Joud M. Boidol B. Mar B. Saksena G. Weinstock D.M. Armstrong S. Ellis S.R. Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations EMBO Mol. Med. 2017 9 498 507 10.15252/emmm.201606660 28264936 PMC5376749

256. Narla A. Ebert B.L. Ribosomopathies: Human disorders of ribosome dysfunction Blood 2010 115 3196 3205 10.1182/blood-2009-10-178129 20194897 PMC2858486

257. Farley-Barnes K.I. Ogawa L.M. Baserga S.J. Ribosomopathies: Old Concepts, New Controversies Trends Genet. 2019 35 754 767 10.1016/j.tig.2019.07.004 31376929 PMC6852887

258. Josephs H.W. Anaemia of Infancy and Early Childhood Medicine 1936 15 307 451 10.1097/00005792-193615030-00001

259. Wlodarski M.W. Vlachos A. Farrar J.E. Da Costa L.M. Kattamis A. Dianzani I. Belendez C. Unal S. Tamary H. Pasauliene R. Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: International consensus statement Lancet Haematol. 2024 11 e368 e382 10.1016/S2352-3026(24)00063-2 38697731 PMC12424227

260. Kawashima N. Oyarbide U. Cipolli M. Bezzerri V. Corey S.J. Shwachman-Diamond syndromes: Clinical, genetic, and biochemical insights from the rare variants Haematologica 2023 108 2594 2605 10.3324/haematol.2023.282949 37226705 PMC10543188

261. Bruzzese A. Martino E.A. Mendicino F. Lucia E. Olivito V. Capodanno I. Neri A. Morabito F. Vigna E. Gentile M. Myelodysplastic syndromes del(5q): Pathogenesis and its therapeutic implications Eur. J. Haematol. 2024 112 860 869 10.1111/ejh.14181 38294126

262. Nassar J.Y. Kefi F. Alhartani M.M. Sultan A.A. Al-Khatib T. Safdar O.Y. Treacher Collins syndrome: A comprehensive review on clinical features, diagnosis, and management J. Fam. Med. Prim. Care 2024 13 4165 4172 10.4103/jfmpc.jfmpc_851_24 39629436 PMC11610811

263. AlSabbagh M.M. Dyskeratosis congenita: A literature review J. Dtsch. Dermatol. Ges. 2020 18 943 967 10.1111/ddg.14268 32930426

264. Armistead J. Patel N. Wu X. Hemming R. Chowdhury B. Basra G.S. Del Bigio M.R. Ding H. Triggs-Raine B. Growth arrest in the ribosomopathy, Bowen-Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression Biochim. Biophys. Acta 2015 1852 1029 1037 10.1016/j.bbadis.2015.02.007 25708872

265. Vakkilainen S. Taskinen M. Makitie O. Immunodeficiency in cartilage-hair hypoplasia: Pathogenesis, clinical course and management Scand. J. Immunol. 2020 92 e12913 10.1111/sji.12913 32506568

266. Freed E.F. Prieto J.L. McCann K.L. McStay B. Baserga S.J. NOL11, implicated in the pathogenesis of North American Indian childhood cirrhosis, is required for pre-rRNA transcription and processing PLoS Genet. 2012 8 e1002892 10.1371/journal.pgen.1002892 22916032 PMC3420923

267. Weaver K.N. Watt K.E. Hufnagel R.B. Navajas Acedo J. Linscott L.L. Sund K.L. Bender P.L. Konig R. Lourenco C.M. Hehr U. Acrofacial Dysostosis, Cincinnati Type, a Mandibulofacial Dysostosis Syndrome with Limb Anomalies, Is Caused by POLR1A Dysfunction Am. J. Hum. Genet. 2015 96 765 774 10.1016/j.ajhg.2015.03.011 25913037 PMC4570288

268. Isidor B. Geffroy L. de Courtivron B. Le Caignec C. Thiel C.T. Mortier G. Cormier-Daire V. David A. Toutain A. A new form of severe spondyloepimetaphyseal dysplasia: Clinical and radiological characterization Am. J. Med. Genet. A 2013 161A 2645 2651 10.1002/ajmg.a.36132 23956136

269. Jacob P. Lindelöf H. Rustad C.F. Sutton V.R. Moosa S. Udupa P. Hammarsjö A. Bhavani G.S. Batkovskyte D. Tveten K. Clinical, genetic and structural delineation of RPL13-related spondyloepimetaphyseal dysplasia suggest extra-ribosomal functions of eL13 npj Genom. Med. 2023 8 39 10.1038/s41525-023-00380-x 37993442 PMC10665555

270. Costantini A. Alm J.J. Tonelli F. Valta H. Huber C. Tran A.N. Daponte V. Kirova N. Kwon Y.U. Bae J.Y. Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy with Spondyloepimetaphyseal Dysplasia J. Bone Miner. Res. 2021 36 283 297 10.1002/jbmr.4177 32916022 PMC7988564

271. Le Caignec C. Ory B. Lamoureux F. O’Donohue M.F. Orgebin E. Lindenbaum P. Teletchea S. Saby M. Hurst A. Nelson K. RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature Am. J. Hum. Genet. 2019 105 1040 1047 10.1016/j.ajhg.2019.09.024 31630789 PMC6849359

272. Reinsch B. Grand K. Lachman R.S. Kim H.K.W. Sanchez-Lara P.A. Expanding the phenotypic spectrum of RPL13-related skeletal dysplasia Am. J. Med. Genet. A 2021 185 2776 2781 10.1002/ajmg.a.61965 33247527

273. Marneros A.G. BMS1 is mutated in aplasia cutis congenita PLoS Genet. 2013 9 e1003573 10.1371/journal.pgen.1003573 23785305 PMC3681727

274. Bryant C.J. Lorea C.F. de Almeida H.L. Jr. Weinert L. Vedolin L. Pinto E.V.F. Baserga S.J. Biallelic splicing variants in the nucleolar 60S assembly factor RBM28 cause the ribosomopathy ANE syndrome Proc. Natl. Acad. Sci. USA 2021 118 e2017777118 10.1073/pnas.2017777118 33941690 PMC8126767

275. Rayinda T. McSweeney S.M. Fassihi H. Fenton D. Liu L. Stefanato C.M. Dand N. McGrath J.A. Tziotzios C. A novel heterozygous missense variant in ribosomal protein L21 associated with familial hypotrichosis simplex Clin. Exp. Dermatol. 2023 48 840 843 10.1093/ced/llad102 36929380

276. Brooks S.S. Wall A.L. Golzio C. Reid D.W. Kondyles A. Willer J.R. Botti C. Nicchitta C.V. Katsanis N. Davis E.E. A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X-linked microcephaly in humans Genetics 2014 198 723 733 10.1534/genetics.114.168211 25316788 PMC4196623

277. Bourque D.K. Hartley T. Nikkel S.M. Pohl D. Tetreault M. Kernohan K.D. Care4Rare Canada C. Dyment D.A. A de novo mutation in RPL10 causes a rare X-linked ribosomopathy characterized by syndromic intellectual disability and epilepsy: A new case and review of the literature Eur. J. Med. Genet. 2018 61 89 93 10.1016/j.ejmg.2017.10.011 29066376

278. Zanni G. Kalscheuer V.M. Friedrich A. Barresi S. Alfieri P. Di Capua M. Haas S.A. Piccini G. Karl T. Klauck S.M. A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia Hum. Mutat. 2015 36 1155 1158 10.1002/humu.22860 26290468

279. Thevenon J. Michot C. Bole C. Nitschke P. Nizon M. Faivre L. Munnich A. Lyonnet S. Bonnefont J.P. Portes V.D. RPL10 mutation segregating in a family with X-linked syndromic Intellectual Disability Am. J. Med. Genet. A 2015 167A 1908 1912 10.1002/ajmg.a.37094 25846674

280. Paolini N.A. Attwood M. Sondalle S.B. Vieira C. van Adrichem A.M. di Summa F.M. O’Donohue M.F. Gleizes P.E. Rachuri S. Briggs J.W. A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism Am. J. Hum. Genet. 2017 100 506 522 10.1016/j.ajhg.2017.01.034 28257692 PMC5339345

281. Long P.A. Theis J.L. Shih Y.H. Maleszewski J.J. Abell Aleff P.C. Evans J.M. Xu X. Olson T.M. Recessive TAF1A mutations reveal ribosomopathy in siblings with end-stage pediatric dilated cardiomyopathy Hum. Mol. Genet. 2017 26 2874 2881 10.1093/hmg/ddx169 28472305 PMC6455043

282. Bolze A. Boisson B. Bosch B. Antipenko A. Bouaziz M. Sackstein P. Chaker-Margot M. Barlogis V. Briggs T. Colino E. Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons Proc. Natl. Acad. Sci. USA 2018 115 E8007 E8016 10.1073/pnas.1805437115 30072435 PMC6112730

283. Ni C. Wei Y. Vona B. Park D. Wei Y. Schmitz D.A. Ding Y. Sakurai M. Ballard E. Li L. A programmed decline in ribosome levels governs human early neurodevelopment Nat. Cell Biol. 2025 27 1240 1255 10.1038/s41556-025-01708-8 40760247 PMC12339376

284. Volejnikova J. Vojta P. Urbankova H. Mojzikova R. Horvathova M. Hochova I. Cermak J. Blatny J. Sukova M. Bubanska E. Czech and Slovak Diamond-Blackfan Anemia (DBA) Registry update: Clinical data and novel causative genetic lesions Blood Cells Mol. Dis. 2020 81 102380 10.1016/j.bcmd.2019.102380 31855845

285. Vlachos A. Muir E. How I treat Diamond-Blackfan anemia Blood 2010 116 3715 3723 10.1182/blood-2010-02-251090 20651069 PMC2981532

286. Iskander D. Roberts I. Rees C. Szydlo R. Alikian M. Neale M. Harrington Y. Kelleher P. Karadimitris A. de la Fuente J. Impaired cellular and humoral immunity is a feature of Diamond-Blackfan anaemia; experience of 107 unselected cases in the United Kingdom Br. J. Haematol. 2019 186 321 326 10.1111/bjh.15915 30980390

287. Minelli A. Nicolis E. Cannioto Z. Longoni D. Perobelli S. Pasquali F. Sainati L. Poli F. Cipolli M. Danesino C. Incidence of Shwachman-Diamond syndrome Pediatr. Blood Cancer 2012 59 1334 1335 10.1002/pbc.24260 22887728

288. Warren A.J. Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome Adv. Biol. Regul. 2018 67 109 127 10.1016/j.jbior.2017.09.002 28942353 PMC6710477

289. Arber D.A. Orazi A. Hasserjian R.P. Borowitz M.J. Calvo K.R. Kvasnicka H.M. Wang S.A. Bagg A. Barbui T. Branford S. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: Integrating morphologic, clinical, and genomic data Blood 2022 140 1200 1228 10.1182/blood.2022015850 35767897 PMC9479031

290. Khoury J.D. Solary E. Abla O. Akkari Y. Alaggio R. Apperley J.F. Bejar R. Berti E. Busque L. Chan J.K.C. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms Leukemia 2022 36 1703 1719 10.1038/s41375-022-01613-1 35732831 PMC9252913

291. Montalban-Bravo G. Kanagal-Shamanna R. Benton C.B. Class C.A. Chien K.S. Sasaki K. Naqvi K. Alvarado Y. Kadia T.M. Ravandi F. Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes Blood Adv. 2020 4 482 495 10.1182/bloodadvances.2019001101 32027746 PMC7013259

292. Beaumont C.A. Dunaway D.J. Padwa B.L. Forrest C. Koudstaal M.J. Caron C. Extracraniofacial anomalies in Treacher Collins syndrome: A multicentre study of 248 patients Int. J. Oral Maxillofac. Surg. 2021 50 1471 1476 10.1016/j.ijom.2021.03.001 33752939

293. Ulhaq Z.S. Nurputra D.K. Soraya G.V. Kurniawati S. Istifiani L.A. Pamungkas S.A. Tse W.K.F. A systematic review on Treacher Collins syndrome: Correlation between molecular genetic findings and clinical severity Clin. Genet. 2023 103 146 155 10.1111/cge.14243 36203321

294. Ratnasamy V. Navaneethakrishnan S. Sirisena N.D. Grüning N.-M. Brandau O. Thirunavukarasu K. Dagnall C.L. McReynolds L.J. Savage S.A. Dissanayake V.H.W. Dyskeratosis congenita with a novel genetic variant in the DKC1 gene: A case report BMC Med. Genet. 2018 19 85 10.1186/s12881-018-0584-y 29801475 PMC5970516

295. Li F. Li W. Qiao X. Xie X. Clinical features of dyskeratosis congenita in mainland China: Case reports and literature review Int. J. Hematol. 2019 109 328 335 10.1007/s12185-018-02582-x 30604317

296. Savage S.A. Dyskeratosis congenita and telomere biology disorders Hematology 2022 2022 637 648 10.1182/hematology.2022000394 36485133 PMC9821046

297. Taskinen M. Ranki A. Pukkala E. Jeskanen L. Kaitila I. Makitie O. Extended follow-up of the Finnish cartilage-hair hypoplasia cohort confirms high incidence of non-Hodgkin lymphoma and basal cell carcinoma Am. J. Med. Genet. A 2008 146A 2370 2375 10.1002/ajmg.a.32478 18698627

298. Thiel C.T. Rauch A. The molecular basis of the cartilage-hair hypoplasia-anauxetic dysplasia spectrum Best Pract. Res. Clin. Endocrinol. Metab. 2011 25 131 142 10.1016/j.beem.2010.08.004 21396580

299. Kostjukovits S. Klemetti P. Valta H. Martelius T. Notarangelo L.D. Seppanen M. Taskinen M. Makitie O. Analysis of clinical and immunologic phenotype in a large cohort of children and adults with cartilage-hair hypoplasia J. Allergy Clin. Immunol. 2017 140 612 614.e5 10.1016/j.jaci.2017.02.016 28284971 PMC5547008

300. Armistead J. Khatkar S. Meyer B. Mark B.L. Patel N. Coghlan G. Lamont R.E. Liu S. Wiechert J. Cattini P.A. Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen-Conradi syndrome Am. J. Hum. Genet. 2009 84 728 739 10.1016/j.ajhg.2009.04.017 19463982 PMC2694972

301. Lowry R.B. Innes A.M. Bernier F.P. McLeod D.R. Greenberg C.R. Chudley A.E. Chodirker B. Marles S.L. Crumley M.J. Loredo-Osti J.C. Bowen-Conradi syndrome: A clinical and genetic study Am. J. Med. Genet. A 2003 120A 423 428 10.1002/ajmg.a.20059 12838567

302. Warda A.S. Freytag B. Haag S. Sloan K.E. Gorlich D. Bohnsack M.T. Effects of the Bowen-Conradi syndrome mutation in EMG1 on its nuclear import, stability and nucleolar recruitment Hum. Mol. Genet. 2016 25 5353 5364 10.1093/hmg/ddw351 27798105 PMC5418833

303. Drouin E. Russo P. Tuchweber B. Mitchell G. Rasquin-Weber A. North American Indian cirrhosis in children: A review of 30 cases J. Pediatr. Gastroenterol. Nutr. 2000 31 395 404 10.1097/00005176-200010000-00013 11045837

304. Chagnon P. Michaud J. Mitchell G. Mercier J. Marion J.F. Drouin E. Rasquin-Weber A. Hudson T.J. Richter A. A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis Am. J. Hum. Genet. 2002 71 1443 1449 10.1086/344580 12417987 PMC378590

305. Wilkins B.J. Lorent K. Matthews R.P. Pack M. p53-mediated biliary defects caused by knockdown of cirh1a, the zebrafish homolog of the gene responsible for North American Indian Childhood Cirrhosis PLoS ONE 2013 8 e77670 10.1371/journal.pone.0077670 24147052 PMC3795688

306. Watt K.E.N. Neben C.L. Hall S. Merrill A.E. Trainor P.A. tp53-dependent and independent signaling underlies the pathogenesis and possible prevention of Acrofacial Dysostosis-Cincinnati type Hum. Mol. Genet. 2018 27 2628 2643 10.1093/hmg/ddy172 29750247 PMC6927876

307. Smallwood K. Watt K.E.N. Ide S. Baltrunaite K. Brunswick C. Inskeep K. Capannari C. Adam M.P. Begtrup A. Bertola D.R. POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies Am. J. Hum. Genet. 2023 110 809 825 10.1016/j.ajhg.2023.03.014 37075751 PMC10183370

308. Bolze A. Mahlaoui N. Byun M. Turner B. Trede N. Ellis S.R. Abhyankar A. Itan Y. Patin E. Brebner S. Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia Science 2013 340 976 978 10.1126/science.1234864 23579497 PMC3677541

309. Griffin J.N. Sondalle S.B. Robson A. Mis E.K. Griffin G. Kulkarni S.S. Deniz E. Baserga S.J. Khokha M.K. RPSA, a candidate gene for isolated congenital asplenia, is required for pre-rRNA processing and spleen formation in Xenopus Development 2018 145 dev166181 10.1242/dev.166181 30337486 PMC6215398

310. Nousbeck J. Spiegel R. Ishida-Yamamoto A. Indelman M. Shani-Adir A. Adir N. Lipkin E. Bercovici S. Geiger D. van Steensel M.A. Alopecia, neurological defects, and endocrinopathy syndrome caused by decreased expression of RBM28, a nucleolar protein associated with ribosome biogenesis Am. J. Hum. Genet. 2008 82 1114 1121 10.1016/j.ajhg.2008.03.014 18439547 PMC2427309

311. Gerton J.L. Faulty ribosome biogenesis underlies the ribosomopathy alopecia, neurological defects, endocrinopathy (ANE) syndrome Proc. Natl. Acad. Sci. USA 2021 118 e2107030118 10.1073/pnas.2107030118 34035178 PMC8214674

312. Warshauer E. Samuelov L. Sarig O. Vodo D. Bindereif A. Kanaan M. Gat U. Fuchs-Telem D. Shomron N. Farberov L. RBM28, a protein deficient in ANE syndrome, regulates hair follicle growth via miR-203 and p63 Exp. Dermatol. 2015 24 618 622 10.1111/exd.12737 25939713

313. Zhou C. Zang D. Jin Y. Wu H. Liu Z. Du J. Zhang J. Mutation in ribosomal protein L21 underlies hereditary hypotrichosis simplex Hum. Mutat. 2011 32 710 714 10.1002/humu.21503 21412954

314. Alter B.P. Giri N. Savage S.A. Rosenberg P.S. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up Haematologica 2018 103 30 39 10.3324/haematol.2017.178111 29051281 PMC5777188

315. Vlachos A. Rosenberg P.S. Atsidaftos E. Alter B.P. Lipton J.M. Incidence of neoplasia in Diamond Blackfan anemia: A report from the Diamond Blackfan Anemia Registry Blood 2012 119 3815 3819 10.1182/blood-2011-08-375972 22362038 PMC3335385

316. Quarello P. Garelli E. Carando A. Cillario R. Brusco A. Giorgio E. Ferrante D. Corti P. Zecca M. Luciani M. A 20-year long term experience of the Italian Diamond-Blackfan Anaemia Registry: RPS and RPL genes, different faces of the same disease? Br. J. Haematol. 2020 190 93 104 10.1111/bjh.16508 32080838

317. Reed H.D. Do H. Weller E. Harris M.H. Reilly C.R. Tsai H.K. Farrar J.E. Lau B.W. Pommert L. Gamper C. Lymphoid malignancies in patients with Shwachman-Diamond syndrome Blood 2025 145 2528 2532 10.1182/blood.2024026507 40090004 PMC12163733

318. Reilly C.R. Shimamura A. Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances Blood 2023 141 1513 1523 10.1182/blood.2022017739 36542827 PMC10082379

319. McGowan K.A. Pang W.W. Bhardwaj R. Perez M.G. Pluvinage J.V. Glader B.E. Malek R. Mendrysa S.M. Weissman I.L. Park C.Y. Reduced ribosomal protein gene dosage and p53 activation in low-risk myelodysplastic syndrome Blood 2011 118 3622 3633 10.1182/blood-2010-11-318584 21788341 PMC3186336

320. Torihara H. Uechi T. Chakraborty A. Shinya M. Sakai N. Kenmochi N. Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia Br. J. Haematol. 2011 152 648 654 10.1111/j.1365-2141.2010.08535.x 21223253

321. Dutt S. Narla A. Lin K. Mullally A. Abayasekara N. Megerdichian C. Wilson F.H. Currie T. Khanna-Gupta A. Berliner N. Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells Blood 2011 117 2567 2576 10.1182/blood-2010-07-295238 21068437 PMC3062351

322. Jaako P. Flygare J. Olsson K. Quere R. Ehinger M. Henson A. Ellis S. Schambach A. Baum C. Richter J. Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia Blood 2011 118 6087 6096 10.1182/blood-2011-08-371963 21989989

323. Moniz H. Gastou M. Leblanc T. Hurtaud C. Cretien A. Lecluse Y. Raslova H. Larghero J. Croisille L. Faubladier M. Primary hematopoietic cells from DBA patients with mutations in RPL11 and RPS19 genes exhibit distinct erythroid phenotype in vitro Cell Death Dis. 2012 3 e356 10.1038/cddis.2012.88 22833095 PMC3406587

324. Jaako P. Debnath S. Olsson K. Zhang Y. Flygare J. Lindstrom M.S. Bryder D. Karlsson S. Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia Leukemia 2015 29 2221 2229 10.1038/leu.2015.128 25987256 PMC4844018

325. Fok W.C. Niero E.L.O. Dege C. Brenner K.A. Sturgeon C.M. Batista L.F.Z. p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita Stem Cell Rep. 2017 9 409 418 10.1016/j.stemcr.2017.06.015 28757166 PMC5550027

326. Danilova N. Gazda H.T. Ribosomopathies: How a common root can cause a tree of pathologies Dis. Model. Mech. 2015 8 1013 1026 10.1242/dmm.020529 26398160 PMC4582105

327. Lu Y.C. Sanada C. Xavier-Ferrucio J. Wang L. Zhang P.X. Grimes H.L. Venkatasubramanian M. Chetal K. Aronow B. Salomonis N. The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification Cell Rep. 2018 25 2083 2093.e4 10.1016/j.celrep.2018.10.084 30463007 PMC6336197

328. Le Goff S. Boussaid I. Floquet C. Raimbault A. Hatin I. Andrieu-Soler C. Salma M. Leduc M. Gautier E.F. Guyot B. p53 activation during ribosome biogenesis regulates normal erythroid differentiation Blood 2021 137 89 102 10.1182/blood.2019003439 32818241

329. Rio S. Gastou M. Karboul N. Derman R. Suriyun T. Manceau H. Leblanc T. El Benna J. Schmitt C. Azouzi S. Regulation of globin-heme balance in Diamond-Blackfan anemia by HSP70/GATA1 Blood 2019 133 1358 1370 10.1182/blood-2018-09-875674 30700418 PMC6428670

330. Pereboeva L. Westin E. Patel T. Flaniken I. Lamb L. Klingelhutz A. Goldman F. DNA damage responses and oxidative stress in dyskeratosis congenita PLoS ONE 2013 8 e76473 10.1371/journal.pone.0076473 24124565 PMC3790691

331. Sulima S.O. Kampen K.R. Vereecke S. Pepe D. Fancello L. Verbeeck J. Dinman J.D. De Keersmaecker K. Ribosomal Lesions Promote Oncogenic Mutagenesis Cancer Res. 2019 79 320 327 10.1158/0008-5472.CAN-18-1987 30482776 PMC7116100

332. Sakai D. Trainor P.A. Face off against ROS: Tcof1/Treacle safeguards neuroepithelial cells and progenitor neural crest cells from oxidative stress during craniofacial development Dev. Growth Differ. 2016 58 577 585 10.1111/dgd.12305 27481486 PMC5026570

333. Rey M.A. Duffy S.P. Brown J.K. Kennedy J.A. Dick J.E. Dror Y. Tailor C.S. Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis Haematologica 2008 93 1617 1626 10.3324/haematol.13359 18815190

334. Zambetti N.A. Ping Z. Chen S. Kenswil K.J.G. Mylona M.A. Sanders M.A. Hoogenboezem R.M. Bindels E.M.J. Adisty M.N. Van Strien P.M.H. Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia Cell Stem Cell 2016 19 613 627 10.1016/j.stem.2016.08.021 27666011

335. Gal Z. Nieto B. Boukoura S. Rasmussen A.V. Larsen D.H. Treacle Sticks the Nucleolar Responses to DNA Damage Together Front. Cell Dev. Biol. 2022 10 892006 10.3389/fcell.2022.892006 35646927 PMC9133508

336. Miller S.C. MacDonald C.C. Kellogg M.K. Karamysheva Z.N. Karamyshev A.L. Specialized Ribosomes in Health and Disease Int. J. Mol. Sci. 2023 24 6334 10.3390/ijms24076334 37047306 PMC10093926

337. Beavan A.J.S. Thuburn V. Fatkhullin B. Cunningham J. Hopes T.S. Dimascio E. Chan T. Zhao N. Norris K. Chau C. Specialized ribosomes: Integrating new insights and current challenges Philos. Trans. R. Soc. Lond. B Biol. Sci. 2025 380 20230377 10.1098/rstb.2023.0377 40045788 PMC11883436

338. Mills E.W. Green R. Ribosomopathies: There’s strength in numbers Science 2017 358 eaan2755 10.1126/science.aan2755 29097519

339. Ludwig L.S. Gazda H.T. Eng J.C. Eichhorn S.W. Thiru P. Ghazvinian R. George T.I. Gotlib J.R. Beggs A.H. Sieff C.A. Altered translation of GATA1 in Diamond-Blackfan anemia Nat. Med. 2014 20 748 753 10.1038/nm.3557 24952648 PMC4087046

340. Khajuria R.K. Munschauer M. Ulirsch J.C. Fiorini C. Ludwig L.S. McFarland S.K. Abdulhay N.J. Specht H. Keshishian H. Mani D.R. Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis Cell 2018 173 90 103.e19 10.1016/j.cell.2018.02.036 29551269 PMC5866246

341. Tiu G.C. Kerr C.H. Forester C.M. Krishnarao P.S. Rosenblatt H.D. Raj N. Lantz T.C. Zhulyn O. Bowen M.E. Shokat L. A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies Dev. Cell 2021 56 2089 2102.e11 10.1016/j.devcel.2021.06.013 34242585 PMC8319123

342. Revy P. Kannengiesser C. Fischer A. Somatic genetic rescue in Mendelian haematopoietic diseases Nat. Rev. Genet. 2019 20 582 598 10.1038/s41576-019-0139-x 31186537

343. Cull A.H. Kent D.G. Warren A.J. Emerging genetic technologies informing personalized medicine in Shwachman-Diamond syndrome and other inherited BMF disorders Blood 2024 144 931 939 10.1182/blood.2023019986 38905596

344. Xia J. Miller C.A. Baty J. Ramesh A. Jotte M.R.M. Fulton R.S. Vogel T.P. Cooper M.A. Walkovich K.J. Makaryan V. Somatic mutations and clonal hematopoiesis in congenital neutropenia Blood 2018 131 408 416 10.1182/blood-2017-08-801985 29092827 PMC5790127

345. Valli R. Pressato B. Marletta C. Mare L. Montalbano G. Curto F.L. Pasquali F. Maserati E. Different loss of material in recurrent chromosome 20 interstitial deletions in Shwachman-Diamond syndrome and in myeloid neoplasms Mol. Cytogenet. 2013 6 56 10.1186/1755-8166-6-56 24330778 PMC3914702

346. Jongmans M.C.J. Diets I.J. Quarello P. Garelli E. Kuiper R.P. Pfundt R. Somatic reversion events point towards RPL4 as a novel disease gene in a condition resembling Diamond-Blackfan anemia Haematologica 2018 103 e607 e609 10.3324/haematol.2018.200683 30213830 PMC6269308

347. Venugopal P. Moore S. Lawrence D.M. George A.J. Hannan R.D. Bray S.C. To L.B. D’Andrea R.J. Feng J. Tirimacco A. Self-reverting mutations partially correct the blood phenotype in a Diamond Blackfan anemia patient Haematologica 2017 102 e506 e509 10.3324/haematol.2017.166678 28971907 PMC5709125

348. Kulasekararaj A.G. Smith A.E. Mian S.A. Mohamedali A.M. Krishnamurthy P. Lea N.C. Gaken J. Pennaneach C. Ireland R. Czepulkowski B. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis Br. J. Haematol. 2013 160 660 672 10.1111/bjh.12203 23297687

349. Scharenberg C. Giai V. Pellagatti A. Saft L. Dimitriou M. Jansson M. Jadersten M. Grandien A. Douagi I. Neuberg D.S. Progression in patients with low- and intermediate-1-risk del(5q) myelodysplastic syndromes is predicted by a limited subset of mutations Haematologica 2017 102 498 508 10.3324/haematol.2016.152025 27884971 PMC5394951

350. Aspesi A. Ellis S.R. Rare ribosomopathies: Insights into mechanisms of cancer Nat. Rev. Cancer 2019 19 228 238 10.1038/s41568-019-0105-0 30670820

351. Tan S. Kermasson L. Hilcenko C. Kargas V. Traynor D. Boukerrou A.Z. Escudero-Urquijo N. Faille A. Bertrand A. Rossmann M. Somatic genetic rescue of a germline ribosome assembly defect Nat. Commun. 2021 12 5044 10.1038/s41467-021-24999-5 34413298 PMC8377010

352. Bretones G. Alvarez M.G. Arango J.R. Rodriguez D. Nadeu F. Prado M.A. Valdes-Mas R. Puente D.A. Paulo J.A. Delgado J. Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia Blood 2018 132 2375 2388 10.1182/blood-2017-09-804401 30181176 PMC6410914

353. Kampen K.R. Sulima S.O. Verbelen B. Girardi T. Vereecke S. Rinaldi G. Verbeeck J. Op de Beeck J. Uyttebroeck A. Meijerink J.P.P. The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL Leukemia 2019 33 319 332 10.1038/s41375-018-0176-z 29930300 PMC6169730

354. Tiku V. Antebi A. Nucleolar Function in Lifespan Regulation Trends Cell Biol. 2018 28 662 672 10.1016/j.tcb.2018.03.007 29779866

355. Kasselimi E. Pefani D.E. Taraviras S. Lygerou Z. Ribosomal DNA and the nucleolus at the heart of aging Trends Biochem. Sci. 2022 47 328 341 10.1016/j.tibs.2021.12.007 35063340

356. Ganley A.R. Kobayashi T. Ribosomal DNA and cellular senescence: New evidence supporting the connection between rDNA and aging FEMS Yeast Res. 2014 14 49 59 10.1111/1567-1364.12133 24373458

357. Mukherjee S. Sinha D. Bhattacharya S. Srinivasan K. Abdisalaam S. Asaithamby A. Werner Syndrome Protein and DNA Replication Int. J. Mol. Sci. 2018 19 3442 10.3390/ijms19113442 30400178 PMC6274846

358. Karikkineth A.C. Scheibye-Knudsen M. Fivenson E. Croteau D.L. Bohr V.A. Cockayne syndrome: Clinical features, model systems and pathways Ageing Res. Rev. 2017 33 3 17 10.1016/j.arr.2016.08.002 27507608 PMC5195851

359. Buchwalter A. Hetzer M.W. Nucleolar expansion and elevated protein translation in premature aging Nat. Commun. 2017 8 328 10.1038/s41467-017-00322-z 28855503 PMC5577202

360. Parlato R. Liss B. How Parkinson’s disease meets nucleolar stress Biochim. Biophys. Acta 2014 1842 791 797 10.1016/j.bbadis.2013.12.014 24412806

361. Rieker C. Engblom D. Kreiner G. Domanskyi A. Schober A. Stotz S. Neumann M. Yuan X. Grummt I. Schutz G. Nucleolar disruption in dopaminergic neurons leads to oxidative damage and parkinsonism through repression of mammalian target of rapamycin signaling J. Neurosci. 2011 31 453 460 10.1523/JNEUROSCI.0590-10.2011 21228155 PMC6623444

362. Hernandez-Ortega K. Garcia-Esparcia P. Gil L. Lucas J.J. Ferrer I. Altered Machinery of Protein Synthesis in Alzheimer’s: From the Nucleolus to the Ribosome Brain Pathol. 2016 26 593 605 10.1111/bpa.12335 26512942 PMC8029302

363. Brooks W.H. Polyamine Dysregulation and Nucleolar Disruption in Alzheimer’s Disease J. Alzheimer’s Dis. 2024 98 837 857 10.3233/jad-231184 38489184 PMC11091575

364. Edvardson S. Nicolae C.M. Agrawal P.B. Mignot C. Payne K. Prasad A.N. Prasad C. Sadler L. Nava C. Mullen T.E. Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood Am. J. Hum. Genet. 2017 101 267 273 10.1016/j.ajhg.2017.07.002 28777933 PMC5544390

365. Herrmann D. Parlato R. C9orf72-associated neurodegeneration in ALS-FTD: Breaking new ground in ribosomal RNA and nucleolar dysfunction Cell Tissue Res. 2018 373 351 360 10.1007/s00441-018-2806-1 29450726

366. Mizielinska S. Ridler C.E. Balendra R. Thoeng A. Woodling N.S. Grasser F.A. Plagnol V. Lashley T. Partridge L. Isaacs A.M. Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration Acta Neuropathol. Commun. 2017 5 29 10.1186/s40478-017-0432-x 28420437 PMC5395972

367. Kwon I. Xiang S. Kato M. Wu L. Theodoropoulos P. Wang T. Kim J. Yun J. Xie Y. McKnight S.L. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells Science 2014 345 1139 1145 10.1126/science.1254917 25081482 PMC4459787

368. Lafarga V. Sirozh O. Diaz-Lopez I. Galarreta A. Hisaoka M. Zarzuela E. Boskovic J. Jovanovic B. Fernandez-Leiro R. Munoz J. Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides EMBO J. 2021 40 e103311 10.15252/embj.2019103311 33978236 PMC8246256

369. Lee J. Hwang Y.J. Ryu H. Kowall N.W. Ryu H. Nucleolar dysfunction in Huntington’s disease Biochim. Biophys. Acta 2014 1842 785 790 10.1016/j.bbadis.2013.09.017 24184605 PMC3972370

370. Lee J. Hwang Y.J. Boo J.H. Han D. Kwon O.K. Todorova K. Kowall N.W. Kim Y. Ryu H. Dysregulation of upstream binding factor-1 acetylation at K352 is linked to impaired ribosomal DNA transcription in Huntington’s disease Cell Death Differ. 2011 18 1726 1735 10.1038/cdd.2011.38 21546905 PMC3154516

371. Kreiner G. Bierhoff H. Armentano M. Rodriguez-Parkitna J. Sowodniok K. Naranjo J.R. Bonfanti L. Liss B. Schütz G. Grummt I. A neuroprotective phase precedes striatal degeneration upon nucleolar stress Cell Death Differ. 2013 20 1455 1464 10.1038/cdd.2013.66 23764776 PMC3792439

372. Ulloa-Aguilar J.M. Herrera Moro Huitron L. Benitez-Zeferino R.Y. Cerna-Cortes J.F. Garcia-Cordero J. Leon-Reyes G. Guzman-Bautista E.R. Farfan-Morales C.N. Reyes-Ruiz J.M. Miranda-Labra R.U. The Nucleolus and Its Interactions with Viral Proteins Required for Successful Infection Cells 2024 13 1591 10.3390/cells13181591 39329772 PMC11430610

373. Salvetti A. Greco A. Viruses and the nucleolus: The fatal attraction Biochim. Biophys. Acta 2014 1842 840 847 10.1016/j.bbadis.2013.12.010 24378568 PMC7135015

374. Merino V.F. Yan Y. Ordonez A.A. Bullen C.K. Lee A. Saeki H. Ray K. Huang T. Jain S.K. Pomper M.G. Nucleolin mediates SARS-CoV-2 replication and viral-induced apoptosis of host cells Antivir. Res. 2023 211 105550 10.1016/j.antiviral.2023.105550 36740097 PMC9896859

375. Naveed A. Umer R. Fatemah A. Naveed R. Nucleolin a Central Player in Host Virus Interactions and its Role in Viral Progeny Production Mol. Biotechnol. 2026 68 33 41 10.1007/s12033-025-01372-1 39821823

376. Hu X. Yin G. Zhang Y. Zhu L. Huang H. Lv K. Recent advances in the functional explorations of nuclear microRNAs Front. Immunol. 2023 14 1097491 10.3389/fimmu.2023.1097491 36911728 PMC9992549

377. Brooks W.H. Viral Impact in Autoimmune Diseases: Expanding the “X Chromosome-Nucleolus Nexus” Hypothesis Front. Immunol. 2017 8 1657 10.3389/fimmu.2017.01657 29234321 PMC5712313

378. Brooks W.H. A Review of Autoimmune Disease Hypotheses with Introduction of the “Nucleolus” Hypothesis Clin. Rev. Allergy Immunol. 2017 52 333 350 10.1007/s12016-016-8567-2 27324247

379. Brooks W.H. Review of the “X chromosome-nucleolus nexus” hypothesis of autoimmune diseases with an update explaining disruption of the nucleolus Immunol. Res. 2018 66 790 799 10.1007/s12026-018-9044-1 30515730

380. Wu S. Chen J. Teo B.H.D. Wee S.Y.K. Wong M.H.M. Cui J. Chen J. Leong K.P. Lu J. The axis of complement C1 and nucleolus in antinuclear autoimmunity Front. Immunol. 2023 14 1196544 10.3389/fimmu.2023.1196544 37359557 PMC10288996

381. Corman A. Sirozh O. Lafarga V. Fernandez-Capetillo O. Targeting the nucleolus as a therapeutic strategy in human disease Trends Biochem. Sci. 2023 48 274 287 10.1016/j.tibs.2022.09.006 36229381

382. Howard G.C. Tansey W.P. Ribosome-directed cancer therapies: The tip of the iceberg? Trends Pharmacol. Sci. 2025 46 303 310 10.1016/j.tips.2025.02.001 40044536 PMC11972149

383. Drygin D. Siddiqui-Jain A. O’Brien S. Schwaebe M. Lin A. Bliesath J. Ho C.B. Proffitt C. Trent K. Whitten J.P. Anticancer Activity of CX-3543: A Direct Inhibitor of rRNA Biogenesis Cancer Res. 2009 69 7653 7661 10.1158/0008-5472.Can-09-1304 19738048

384. Yao Y.X. Xu B.H. Zhang Y. CX-3543 Promotes Cell Apoptosis through Downregulation of CCAT1 in Colon Cancer Cells BioMed Res. Int. 2018 2018 9701957 10.1155/2018/9701957 30519593 PMC6241339

385. Jacobs R.Q. Huffines A.K. Laiho M. Schneider D.A. The small-molecule BMH-21 directly inhibits transcription elongation and DNA occupancy of RNA polymerase I in vivo and in vitro J. Biol. Chem. 2022 298 101450 10.1016/j.jbc.2021.101450 34838819 PMC8683726

386. Peltonen K. Colis L. Liu H. Trivedi R. Moubarek M.S. Moore H.M. Bai B. Rudek M.A. Bieberich C.J. Laiho M. A targeting modality for destruction of RNA polymerase I that possesses anticancer activity Cancer Cell 2014 25 77 90 10.1016/j.ccr.2013.12.009 24434211 PMC3930145

387. Drygin D. Lin A. Bliesath J. Ho C.B. O’Brien S.E. Proffitt C. Omori M. Haddach M. Schwaebe M.K. Siddiqui-Jain A. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth Cancer Res. 2011 71 1418 1430 10.1158/0008-5472.CAN-10-1728 21159662

388. Khot A. Brajanovski N. Cameron D.P. Hein N. Maclachlan K.H. Sanij E. Lim J. Soong J. Link E. Blombery P. First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study Cancer Discov. 2019 9 1036 1049 10.1158/2159-8290.CD-18-1455 31092402

389. Hilton J. Gelmon K. Bedard P.L. Tu D. Xu H. Tinker A.V. Goodwin R. Laurie S.A. Jonker D. Hansen A.R. Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies Nat. Commun. 2022 13 3607 10.1038/s41467-022-31199-2 35750695 PMC9232501

390. Lee H.C. Wang H. Baladandayuthapani V. Lin H. He J. Jones R.J. Kuiatse I. Gu D. Wang Z. Ma W. RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma Br. J. Haematol. 2017 177 80 94 10.1111/bjh.14525 28369725 PMC5695568

391. Xu H. Di Antonio M. McKinney S. Mathew V. Ho B. O’Neil N.J. Santos N.D. Silvester J. Wei V. Garcia J. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours Nat. Commun. 2017 8 14432 10.1038/ncomms14432 28211448 PMC5321743

392. Sanij E. Hannan K.M. Xuan J. Yan S. Ahern J.E. Trigos A.S. Brajanovski N. Son J. Chan K.T. Kondrashova O. CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer Nat. Commun. 2020 11 2641 10.1038/s41467-020-16393-4 32457376 PMC7251123

393. Yan S. Xuan J. Brajanovski N. Tancock M.R.C. Madhamshettiwar P.B. Simpson K.J. Ellis S. Kang J. Cullinane C. Sheppard K.E. The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer Br. J. Cancer 2021 124 616 627 10.1038/s41416-020-01158-z 33173151 PMC7851142

394. Rebello R.J. Kusnadi E. Cameron D.P. Pearson H.B. Lesmana A. Devlin J.R. Drygin D. Clark A.K. Porter L. Pedersen J. The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer Clin. Cancer Res. 2016 22 5539 5552 10.1158/1078-0432.CCR-16-0124 27486174

395. Li H.X. He Y.M. Fei J. Guo M. Zeng C. Yan P.J. Xu Y. Qin G. Teng F.Y. The G-quadruplex ligand CX-5461: An innovative candidate for disease treatment J. Transl. Med. 2025 23 457 10.1186/s12967-025-06473-8 40251554 PMC12007140

396. Mars J.C. Tremblay M.G. Valere M. Sibai D.S. Sabourin-Felix M. Lessard F. Moss T. The chemotherapeutic agent CX-5461 irreversibly blocks RNA polymerase I initiation and promoter release to cause nucleolar disruption, DNA damage and cell inviability NAR Cancer 2020 2 zcaa032 10.1093/narcan/zcaa032 33196044 PMC7646227

397. Bruno P.M. Lu M. Dennis K.A. Inam H. Moore C.J. Sheehe J. Elledge S.J. Hemann M.T. Pritchard J.R. The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning Proc. Natl. Acad. Sci. USA 2020 117 4053 4060 10.1073/pnas.1921649117 32041867 PMC7049172

398. Bossaert M. Pipier A. Riou J.F. Noirot C. Nguyen L.T. Serre R.F. Bouchez O. Defrancq E. Calsou P. Britton S. Transcription-associated topoisomerase 2alpha (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands eLife 2021 10 e65184 10.7554/eLife.65184 34180392 PMC8279764

399. Cameron D.P. Sornkom J. Alsahafi S. Drygin D. Poortinga G. McArthur G.A. Hein N. Hannan R. Panov K.I. CX-5461 Preferentially Induces Top2alpha-Dependent DNA Breaks at Ribosomal DNA Loci Biomedicines 2024 12 1514 10.3390/biomedicines12071514 39062087 PMC11275095

400. Koh G.C.C. Boushaki S. Zhao S.J. Pregnall A.M. Sadiyah F. Badja C. Memari Y. Georgakopoulos-Soares I. Nik-Zainal S. The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells Nat. Genet. 2024 56 23 26 10.1038/s41588-023-01602-9 38036782 PMC10786719

401. Ferreira R. Hannan K.M. Panov K. Udumanne T. George A.J. Closa A. Yuen Z. Eyras E. Poh P. Maclachlan K. The novel RNA polymerase I transcription inhibitor PMR-116 exploits a critical therapeutic vulnerability in a broad-spectrum of high MYC malignancies bioRxiv 2025 2025.2004.2019.649466 10.1101/2025.04.19.649466

402. Furic L. Ferreira R. Hannan K. Kusnadi E. Panov K. George A. Huglo A. Lawrence M. Tran B. Desai J. 77P PMR-116, a second generation ribosome biogenesis inhibitor, displays antitumour activity in a wide range of preclinical cancer models and on-target activity in a phase I trial ESMO Open 2025 10 105427 10.1016/j.esmoop.2025.105427

403. Orgebin E. Lamoureux F. Isidor B. Charrier C. Ory B. Lezot F. Baud’huin M. Ribosomopathies: New Therapeutic Perspectives Cells 2020 9 2080 10.3390/cells9092080 32932838 PMC7564184

404. Iskander D. Wang G. Heuston E.F. Christodoulidou C. Psaila B. Ponnusamy K. Ren H. Mokhtari Z. Robinson M. Chaidos A. Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia Sci. Transl. Med. 2021 13 eabf0113 10.1126/scitranslmed.abf0113 34516827

405. Wang B. Wang C. Wan Y. Gao J. Ma Y. Zhang Y. Tong J. Zhang Y. Liu J. Chang L. Decoding the pathogenesis of Diamond-Blackfan anemia using single-cell RNA-seq Cell Discov. 2022 8 41 10.1038/s41421-022-00389-z 35534476 PMC9085895

406. Maceckova Z. Kubickova A. De Sanctis J.B. Hajduch M. Effect of Glucocorticosteroids in Diamond-Blackfan Anaemia: Maybe Not as Elusive as It Seems Int. J. Mol. Sci. 2022 23 1886 10.3390/ijms23031886 35163808 PMC8837118

407. Ashley R.J. Yan H. Wang N. Hale J. Dulmovits B.M. Papoin J. Olive M.E. Udeshi N.D. Carr S.A. Vlachos A. Steroid resistance in Diamond Blackfan anemia associates with p57Kip2 dysregulation in erythroid progenitors J. Clin. Investig. 2020 130 2097 2110 10.1172/JCI132284 31961825 PMC7108903

408. Da Costa L. Narla A. Mohandas N. An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia F1000Research 2018 7 1350 10.12688/f1000research.15542.1 30228860 PMC6117846

409. Aljebab F. Choonara I. Conroy S. Systematic Review of the Toxicity of Long-Course Oral Corticosteroids in Children PLoS ONE 2017 12 e0170259 10.1371/journal.pone.0170259 28125632 PMC5268779

410. Liu Z. Ting Y. Li M. Li Y. Tan Y. Long Y. From immune dysregulation to organ dysfunction: Understanding the enigma of Sepsis Front. Microbiol. 2024 15 1415274 10.3389/fmicb.2024.1415274 39252831 PMC11381394

411. Kumar J. Lewis N.E. Sherpa S. Londono D. Sun X. Gao Q. Arcila M.E. Roshal M. Zhang Y. Xiao W. Diagnostic challenges and proposed classification of myeloid neoplasms with overlapping features of thrombocytosis, ring sideroblasts and concurrent del(5q) and SF3B1 mutations Haematologica 2024 109 2676 2681 10.3324/haematol.2023.284599 38572547 PMC11290515

412. Han X. Lu S. Gu C. Bian Z. Xie X. Qiao X. Clinical features, epidemiology, and treatment of Shwachman-Diamond syndrome: A systematic review BMC Pediatr. 2023 23 503 10.1186/s12887-023-04324-3 37803383 PMC10557232

413. Coates T.D. Management of iron overload: Lessons from transfusion-dependent hemoglobinopathies Blood 2025 145 359 371 10.1182/blood.2023022502 39293029

414. Vlachos A. Atsidaftos E. Lababidi M.L. Muir E. Rogers Z.R. Alhushki W. Bernstein J. Glader B. Gruner B. Hartung H. L-leucine improves anemia and growth in patients with transfusion-dependent Diamond-Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond-Blackfan Anemia Registry Pediatr. Blood Cancer 2020 67 e28748 10.1002/pbc.28748 33025707 PMC8273758

415. Jaako P. Debnath S. Olsson K. Bryder D. Flygare J. Karlsson S. Dietary L-leucine improves the anemia in a mouse model for Diamond-Blackfan anemia Blood 2012 120 2225 2228 10.1182/blood-2012-05-431437 22791294

416. Payne E.M. Virgilio M. Narla A. Sun H. Levine M. Paw B.H. Berliner N. Look A.T. Ebert B.L. Khanna-Gupta A. L-Leucine improves the anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q) MDS by activating the mTOR pathway Blood 2012 120 2214 2224 10.1182/blood-2011-10-382986 22734070 PMC3447780

417. Taylor A.M. Macari E.R. Chan I.T. Blair M.C. Doulatov S. Vo L.T. Raiser D.M. Siva K. Basak A. Pirouz M. Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia Sci. Transl. Med. 2020 12 eabb5831 10.1126/scitranslmed.abb5831 33087503 PMC7709865

418. Choudhuri A. Corry H. Lucas B. Luehr G. Matson D. Stuart B. Patel-Hett S. McGrath L. Zhou Y. Gunage R. First-in-class small molecule calmodulin pathway modulators attenuate excess p53 activity and correct erythropoietic defects in models of diamond-blackfan anemia (DBA) Blood 2025 146 1441 10.1182/blood-2025-1441

419. Duncan B.B. Lotter J. Superata J. Barranta M.E. Darden I. Venugopal S. Wu C.O. Dunbar C.E. Young D.J. Treatment of Refractory Diamond-Blackfan Anemia with Eltrombopag Blood 2022 140 5824 5825 10.1182/blood-2022-160297 PMC11212774 38462764

420. Duncan B.B. Lotter J.L. Superata J. Barranta M.E. Machado T. Darden I. Venugopal S. Wu C.O. Abkowitz J.L. Dunbar C.E. Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag Br. J. Haematol. 2024 204 2077 2085 10.1111/bjh.19357 38462764 PMC11212774

421. Bezzerri V. Pegoraro A. Hristodor A.M. Crane G.M. Meneghelli I. Brignole C. Boni C. Baldisseri E. Vella A. Menichetti G. Ataluren improves hematopoietic and pancreatic disorders in Shwachman-Diamond syndrome patients: A compassionate program case-series Nat. Commun. 2025 16 8189 10.1038/s41467-025-63137-3 40897730 PMC12405498

422. Kirschner M. Vieri M. Kricheldorf K. Ferreira M.S.V. Wlodarski M.W. Schwarz M. Balabanov S. Rolles B. Isfort S. Koschmieder S. Androgen derivatives improve blood counts and elongate telomere length in adult cryptic dyskeratosis congenita Br. J. Haematol. 2021 193 669 673 10.1111/bjh.16997 32744739

423. Khincha P.P. Wentzensen I.M. Giri N. Alter B.P. Savage S.A. Response to androgen therapy in patients with dyskeratosis congenita Br. J. Haematol. 2014 165 349 357 10.1111/bjh.12748 24666134 PMC3984599

424. Myers K.C. Davies S.M. Lutzko C. Wahle R. Grier D.D. Aubert G. Norris K. Baird D.M. Koga M. Ko A.C. Clinical Use of ZSCAN4 for Telomere Elongation in Hematopoietic Stem Cells NEJM Evid. 2025 4 EVIDoa2400252 10.1056/EVIDoa2400252 39998303

425. Siva K. Ek F. Chen J. Ghani Alattar A. Sigmundsson K. Olsson R. Wlodarski M. Lundback T. Flygare J. A Phenotypic Screening Assay Identifies Modulators of Diamond Blackfan Anemia SLAS Discov. 2019 24 304 313 10.1177/2472555218823531 30784369

426. Wilkes M.C. Siva K. Chen J. Varetti G. Youn M.Y. Chae H. Ek F. Olsson R. Lundbäck T. Dever D.P. Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase Nat. Commun. 2020 11 3344 10.1038/s41467-020-17100-z 32620751 PMC7334220

427. Strahm B. Loewecke F. Niemeyer C.M. Albert M. Ansari M. Bader P. Bertrand Y. Burkhardt B. Da Costa L.M. Ferster A. Favorable outcomes of hematopoietic stem cell transplantation in children and adolescents with Diamond-Blackfan anemia Blood Adv. 2020 4 1760 1769 10.1182/bloodadvances.2019001210 32343795 PMC7189291

428. Ma C. Huang X. Chen Y. Shi F. Li X. Tian S. Ma W. Outcomes of allogeneic hematopoietic stem cell transplantation in Shwachman-Diamond syndrome: A systematic review and meta-analysis Cytotherapy 2025 27 465 474 10.1016/j.jcyt.2024.12.004 39745406

429. Qimudesiren Yin W. Wang Y. Qing G. Bao J. Chaomurilige Chen S. Qian L. Hematopoietic Stem Cell Transplantation in the Management of Myelodysplastic Syndrome: A Retrospective, Current, and Future Perspective Cell Transplant. 2024 33 9636897241284283 10.1177/09636897241284283 39374074 PMC11483824

430. Fioredda F. Iacobelli S. Korthof E.T. Knol C. van Biezen A. Bresters D. Veys P. Yoshimi A. Fagioli F. Mats B. Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita Br. J. Haematol. 2018 183 110 118 10.1111/bjh.15495 29984823

431. Bordon V. Gennery A.R. Slatter M.A. Vandecruys E. Laureys G. Veys P. Qasim W. Friedrich W. Wulfraat N.M. Scherer F. Clinical and immunologic outcome of patients with cartilage hair hypoplasia after hematopoietic stem cell transplantation Blood 2010 116 27 35 10.1182/blood-2010-01-259168 20375313

432. Fathi P. Jafari L. Fathi A. Ahmadi A. Karamlou Y. Behfar M. Hamidieh A.A. Hematopoietic Stem Cell Transplantation Outcomes in Diamond-Blackfan Anemia Patients Based on Myeloablative Conditioning Regimen With or Without Total Body Irradiation: A Systematic Review and Meta-Analysis EJHaem 2025 6 e70043 10.1002/jha2.70043 40342615 PMC12061074

433. Sayed N. Allawadhi P. Khurana A. Singh V. Navik U. Pasumarthi S.K. Khurana I. Banothu A.K. Weiskirchen R. Bharani K.K. Gene therapy: Comprehensive overview and therapeutic applications Life Sci. 2022 294 120375 10.1016/j.lfs.2022.120375 35123997

434. Liu Y. Dahl M. Debnath S. Rothe M. Smith E.M. Grahn T.H.M. Warsi S. Chen J. Flygare J. Schambach A. Successful gene therapy of Diamond-Blackfan anemia in a mouse model and human CD34(+) cord blood hematopoietic stem cells using a clinically applicable lentiviral vector Haematologica 2022 107 446 456 10.3324/haematol.2020.269142 33440921 PMC8804567

435. Bhoopalan S.V. Mayuranathan T. Liu N. Mayberry K. Yao Y. Zhang J. Metais J.Y. Yan K.K. Throm R.E. Ellis S.R. Preclinical development of lentiviral vector gene therapy for Diamond-Blackfan anemia syndrome Mol. Ther. 2024 33 3086 3100 10.1016/j.ymthe.2024.12.020 39673126 PMC12265966

436. Gimenez Y. Palacios M. Sanchez-Dominguez R. Zorbas C. Peral J. Puzik A. Ugalde L. Alberquilla O. Villanueva M. Rio P. Lentivirus-mediated gene therapy corrects ribosomal biogenesis and shows promise for Diamond Blackfan anemia JCI Insight 2024 9 e171650 10.1172/jci.insight.171650 38775150 PMC11141922

437. Debnath S. Jaako P. Siva K. Rothe M. Chen J. Dahl M. Gaspar H.B. Flygare J. Schambach A. Karlsson S. Lentiviral Vectors with Cellular Promoters Correct Anemia and Lethal Bone Marrow Failure in a Mouse Model for Diamond-Blackfan Anemia Mol. Ther. 2017 25 1805 1814 10.1016/j.ymthe.2017.04.002 28434866 PMC5542636

438. Voit R.A. Liao X. Caulier A. Antoszewski M. Cohen B. Armant M. Lu H.Y. Fleming T.J. Kamal E. Wahlster L. Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia Cell Stem Cell 2025 32 38 52.e36 10.1016/j.stem.2024.10.012 39532107 PMC11698655

439. Suryaprakash S. Han L. Manquen G. Katta V. Krzyzanowski D. Prasad J. Nimmagada N. Mayberry K. Liu N. Ju Y. Adenine Base Editing Improves Erythropoiesis in Diamond-Blackfan Anemia Syndrome Patient-Derived Induced Pluripotent Stem Cells Blood 2024 144 4088 10.1182/blood-2024-209312

440. Antoniou P. Miccio A. Brusson M. Base and Prime Editing Technologies for Blood Disorders Front. Genome Ed. 2021 3 618406 10.3389/fgeed.2021.618406 34713251 PMC8525391

441. Qin S. Tang X. Chen Y. Chen K. Fan N. Xiao W. Zheng Q. Li G. Teng Y. Wu M. mRNA-based therapeutics: Powerful and versatile tools to combat diseases Signal Transduct. Target. Ther. 2022 7 166 10.1038/s41392-022-01007-w 35597779 PMC9123296

442. Metkar M. Pepin C.S. Moore M.J. Tailor made: The art of therapeutic mRNA design Nat. Rev. Drug Discov. 2024 23 67 83 10.1038/s41573-023-00827-x 38030688

443. Rohner E. Yang R. Foo K.S. Goedel A. Chien K.R. Unlocking the promise of mRNA therapeutics Nat. Biotechnol. 2022 40 1586 1600 10.1038/s41587-022-01491-z 36329321

444. Parhiz H. Atochina-Vasserman E.N. Weissman D. mRNA-based therapeutics: Looking beyond COVID-19 vaccines Lancet 2024 403 1192 1204 10.1016/S0140-6736(23)02444-3 38461842

445. Breda L. Papp T.E. Triebwasser M.P. Yadegari A. Fedorky M.T. Tanaka N. Abdulmalik O. Pavani G. Wang Y. Grupp S.A. In vivo hematopoietic stem cell modification by mRNA delivery Science 2023 381 436 443 10.1126/science.ade6967 37499029 PMC10567133

446. Shi D. Toyonaga S. Anderson D.G. In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles Nano Lett. 2023 23 2938 2944 10.1021/acs.nanolett.3c00304 36988645 PMC10103292

447. Palanki R. Riley J.S. Bose S.K. Luks V. Dave A. Kus N. White B.M. Ricciardi A.S. Swingle K.L. Xue L. In utero delivery of targeted ionizable lipid nanoparticles facilitates in vivo gene editing of hematopoietic stem cells Proc. Natl. Acad. Sci. USA 2024 121 e2400783121 10.1073/pnas.2400783121 39078677 PMC11317576

448. Banda O. Adams S.E. Omer L. Jung S.K. Said H. Phoka T. Tam Y. Weissman D. Rivella S. Alameh M.G. Restoring hematopoietic stem and progenitor cell function in Fancc (−/−) mice by in situ delivery of RNA lipid nanoparticles Mol. Ther. Nucleic Acids 2025 36 102423 10.1016/j.omtn.2024.102423 39811495 PMC11730543

449. Xu S. Liang D. Wang Q. Cheng Y. Xie D. Gui Y. Zhang H. Feng C. Zhao F. Ren W. In vivo genome editing of human hematopoietic stem cells for treatment of blood disorders by mRNA delivery bioRxiv 2024 2024.2010.2028.620445 10.1101/2024.10.28.620445 40796944

450. Alvarez D. Masse-Ranson G. Sedimbi S.K. Wisti P. Rodriguez L. Santana J. Manning T. Towner T. Geilich B. Mihai C. Functional mRNA delivery to hematopoietic stem and progenitor cells in vivo bioRxiv 2022 2022.2012.2015.520650 10.1101/2022.12.15.520650

451. Kim H. Zenhausern R. Gentry K. Lian L. Huayamares S.G. Radmand A. Loughrey D. Podilapu A.R. Hatit M.Z.C. Ni H. Lipid nanoparticle-mediated mRNA delivery to CD34(+) cells in rhesus monkeys Nat. Biotechnol. 2024 43 1813 1820 10.1038/s41587-024-02470-2 39578569 PMC12095617

452. Arjunan P. Mahalingam G. Sankar P. Kathirvelu D. Suresh S. Rani S. Mohankumar K.M. Thangavel S. Marepally S. Base-modified factor VIII mRNA delivery with galactosylated lipid nanoparticles as a protein replacement therapy for haemophilia A Biomater. Sci. 2024 12 5052 5062 10.1039/d4bm00909f 39210734

453. Ramaswamy S. Tonnu N. Tachikawa K. Limphong P. Vega J.B. Karmali P.P. Chivukula P. Verma I.M. Systemic delivery of factor IX messenger RNA for protein replacement therapy Proc. Natl. Acad. Sci. USA 2017 114 E1941 E1950 10.1073/pnas.1619653114 28202722 PMC5347596

454. Liu-Chen S. Connolly B. Cheng L. Subramanian R.R. Han Z. mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice Sci. Rep. 2018 8 7859 10.1038/s41598-018-26298-4 29777164 PMC5959889

455. Popovitz J. Sharma R. Hoshyar R. Soo Kim B. Murthy N. Lee K. Gene editing therapeutics based on mRNA delivery Adv. Drug Deliv. Rev. 2023 200 115026 10.1016/j.addr.2023.115026 37516409

456. Musunuru K. Grandinette S.A. Wang X. Hudson T.R. Briseno K. Berry A.M. Hacker J.L. Hsu A. Silverstein R.A. Hille L.T. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease N. Engl. J. Med. 2025 392 2235 2243 10.1056/NEJMoa2504747 40373211 PMC12713542

457. Liu C. Shi Q. Huang X. Koo S. Kong N. Tao W. mRNA-based cancer therapeutics Nat. Rev. Cancer 2023 23 526 543 10.1038/s41568-023-00586-2 37311817

458. Kong N. Tao W. Ling X. Wang J. Xiao Y. Shi S. Ji X. Shajii A. Gan S.T. Kim N.Y. Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition Sci. Transl. Med. 2019 11 eaaw1565 10.1126/scitranslmed.aaw1565 31852795 PMC7024563

459. Xiao Y. Chen J. Zhou H. Zeng X. Ruan Z. Pu Z. Jiang X. Matsui A. Zhu L. Amoozgar Z. Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy Nat. Commun. 2022 13 758 10.1038/s41467-022-28279-8 35140208 PMC8828745

460. Lin Y.X. Wang Y. Ding J. Jiang A. Wang J. Yu M. Blake S. Liu S. Bieberich C.J. Farokhzad O.C. Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models Sci. Transl. Med. 2021 13 eaba9772 10.1126/scitranslmed.aba9772 34162754 PMC8284983

461. Kong N. Zhang R. Wu G. Sui X. Wang J. Kim N.Y. Blake S. De D. Xie T. Cao Y. Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer Proc. Natl. Acad. Sci. USA 2022 119 e2112696119 10.1073/pnas.2112696119 35131941 PMC8851555

462. Doi A. Delaney C. Tanner D. Burkhart K. Bell R.D. RNA exon editing: Splicing the way to treat human diseases Mol. Ther. Nucleic Acids 2024 35 102311 10.1016/j.omtn.2024.102311 39281698 PMC11401238

463. Zhu G. Zhou X. Wen M. Qiao J. Li G. Yao Y. CRISPR–Cas13: Pioneering RNA Editing for Nucleic Acid Therapeutics BioDesign Res. 2024 6 0041 10.34133/bdr.0041 39228750 PMC11371277

464. Wang P. Sen R. Buchholz F. Sayed S. A base editing platform for the correction of cancer driver mutations unmasks conserved p53 transcription programs Genome Biol. 2025 26 217 10.1186/s13059-025-03667-7 40696461 PMC12285138

465. Fan N. Bian X. Li M. Chen J. Wu H. Peng Q. Bai H. Cheng W. Kong L. Ding S. Hierarchical self-uncloaking CRISPR-Cas13a–customized RNA nanococoons for spatial-controlled genome editing and precise cancer therapy Sci. Adv. 2022 8 eabn7382 10.1126/sciadv.abn7382 35584220 PMC9116607

466. Booth B.J. Nourreddine S. Katrekar D. Savva Y. Bose D. Long T.J. Huss D.J. Mali P. RNA editing: Expanding the potential of RNA therapeutics Mol. Ther. 2023 31 1533 1549 10.1016/j.ymthe.2023.01.005 36620962 PMC9824937

467. Wang S. Weissman D. Dong Y. RNA chemistry and therapeutics Nat. Rev. Drug Discov. 2025 24 828 851 10.1038/s41573-025-01237-x 40659813 PMC12514552

468. Lauffer M.C. van Roon-Mom W. Aartsma-Rus A. Collaborative N. Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders Commun. Med. 2024 4 6 10.1038/s43856-023-00419-1 38182878 PMC10770028

469. Zhang C. Huang R. Ren L. Martincuks A. Song J. Kortylewski M. Swiderski P. Forman S.J. Yu H. Local CpG-Stat3 siRNA treatment improves antitumor effects of immune checkpoint inhibitors Mol. Ther. Nucleic Acids 2024 35 102357 10.1016/j.omtn.2024.102357 39618825 PMC11605413

470. Bennett G. Riedl J. Mudd G. Unlocking the potential of EphA2 with precision-guided cancer therapy: Bicycle drug conjugates J. Transl. Med. 2026 24 322 10.1186/s12967-026-07870-3 41782030 PMC12961899

471. Cina C. Majeti B. O’Brien Z. Wang L. Clamme J.P. Adami R. Tsang K.Y. Harborth J. Ying W. Zabludoff S. A Novel Lipid Nanoparticle NBF-006 Encapsulating Glutathione S-Transferase P siRNA for the Treatment of KRAS-Driven Non–small Cell Lung Cancer Mol. Cancer Ther. 2025 24 7 17 10.1158/1535-7163.Mct-23-0915 39417782

472. Tolcher A.W. Spira A.I. Nemunaitis J.J. Vandross A.L. Mamdani H. O’Brien Z. Huynh A. Albaugh Z. Gullbo J. Zabludoff S. First-in-human dose-escalation study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with non-small cell lung, pancreatic, or colorectal cancer J. Clin. Oncol. 2023 41 3084 10.1200/JCO.2023.41.16_suppl.3084

473. Molyneaux M. Berman B. Xu J. Evans D.M. Lu P.Y. 15580 Effect of TGF-β1/COX- 2 small interfering RNA combination product (STP705) on cell viability and tumor growth in a human squamous carcinoma xenograft tumor model in nude mice J. Am. Acad. Dermatol. 2020 83 AB156 10.1016/j.jaad.2020.06.712

474. Xiao B. Wang S. Pan Y. Zhi W. Gu C. Guo T. Zhai J. Li C. Chen Y.Q. Wang R. Development, opportunities, and challenges of siRNA nucleic acid drugs Mol. Ther. Nucleic Acids 2025 36 102437 10.1016/j.omtn.2024.102437 39897581 PMC11787428

475. Cuiffo B. Maxwell M. Yan D. Guemiri R. Boone A. Bellet D. Rivest B. Cardia J. Robert C. Fricker S.P. Self-delivering RNAi immunotherapeutic PH-762 silences PD-1 to generate local and abscopal antitumor efficacy Front. Immunol. 2024 15 1501679 10.3389/fimmu.2024.1501679 39697325 PMC11652358

476. Cuiffo B. Maxwell M. Yan D. Zhou S. Rivest B. Boone A. Cardia J. Fricker S.P. Abstract 4237: Local administration of BRD4-targeting self-delivering RNAi (PH-894) provides abscopal efficacy toward untreated distal tumors and potentiates the efficacy of systemic anti-PD-1 antibody therapy Cancer Res. 2022 82 4237 10.1158/1538-7445.Am2022-4237

477. Kumthekar P. Ko C.H. Paunesku T. Dixit K. Sonabend A.M. Bloch O. Tate M. Schwartz M. Zuckerman L. Lezon R. A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma Sci. Transl. Med. 2021 13 eabb3945 10.1126/scitranslmed.abb3945 33692132 PMC8272521

478. El Dika I. Lim H.Y. Yong W.P. Lin C.C. Yoon J.H. Modiano M. Freilich B. Choi H.J. Chao T.Y. Kelley R.K. An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma Oncologist 2019 24 747 e218 10.1634/theoncologist.2018-0838 30598500 PMC6656521

479. Alagesan B. Varghese A.M. Ang C. Gutierrez M. Kamar M. Passhak M. Geva R. Yarom N. Lahav M. Ligresti R. A Phase II Trial of an Extended-Release siRNA Implant Targeting KRASG12D/V in Locally Advanced Pancreatic Cancer Clin. Cancer Res. 2026 32 1059 1067 10.1158/1078-0432.Ccr-25-3189 41528981 PMC13380262

480. Narasipura E.A. VanKeulen-Miller R. Ma Y. Fenton O.S. Ongoing Clinical Trials of Nonviral siRNA Therapeutics Bioconjugate Chem. 2023 34 1177 1197 10.1021/acs.bioconjchem.3c00205 37431859

481. Hu B. Zhong L. Weng Y. Peng L. Huang Y. Zhao Y. Liang X.-J. Therapeutic siRNA: State of the art Signal Transduct. Target. Ther. 2020 5 101 10.1038/s41392-020-0207-x 32561705 PMC7305320

482. Gonzalez J.C. Park K.W. Evans D.B. Sharma R. Sahaym O. Gopalakrishnan S. Dar A.I. Valdez T.A. Sharma A. Nano Approaches to Nucleic Acid Delivery: Barriers, Solutions, and Current Landscape Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2025 17 e70010 10.1002/wnan.70010 40223402 PMC11994986

483. Bian X. Zhou L. Luo Z. Liu G. Hang Z. Li H. Li F. Wen Y. Emerging Delivery Systems for Enabling Precision Nucleic Acid Therapeutics ACS Nano 2025 19 4039 4083 10.1021/acsnano.4c11858 39834294

484. Murugesan R. Karuppusamy K.V. Marepally S. Thangavel S. Current approaches and potential challenges in the delivery of gene editing cargos into hematopoietic stem and progenitor cells Front. Genome Ed. 2023 5 1148693 10.3389/fgeed.2023.1148693 37780116 PMC10540692