Frontiers in oncology · 2026
SPRTN preserves RNA polymerase I transcription under genotoxic drug stress in lung adenocarcinoma.
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Sharma Mansi, Karnati Srikanth, Ergün Süleyman, Naidu Srivatsava
Аннотация
BACKGROUND: Hyperactivated RNA polymerase I (Pol I)-driven ribosomal DNA (rDNA) transcription sustains malignant growth and chemotherapy tolerance in lung adenocarcinoma (LUAD). Genotoxic chemotherapeutics such as doxorubicin and cisplatin preferentially damage rDNA by inducing DNA-protein crosslinks (DPCs), yet how tumor cells preserve Pol I transcriptional output under this damage remains poorly understood.
METHODS: We investigated SPRTN function in LUAD using complementary approaches spanning molecular, cellular, and in vivo levels, including DNA-protein crosslink isolation, chromatin immunoprecipitation, nascent RNA synthesis assays, apoptosis and invasion assays in SPRTN loss- and gain-of-function cell models, mouse xenograft studies, and transcriptomic analysis of clinical LUAD datasets.
RESULTS: SPRTN was enriched at the rDNA promoter, limited basal DPC accumulation, sustained Pol I transcriptional output, suppressed the p53-p21 nucleolar stress checkpoint, and promoted Pol I-dependent proliferation. Under doxorubicin or cisplatin treatment, SPRTN was recruited to G-quadruplex-rich rDNA promoters, a process associated with PARP-1 co-recruitment, and facilitated DPC resolution and transcriptional recovery. Catalytically inactive SPRTN failed to resolve rDNA-DPCs and restore Pol I output under both basal and drug-treated conditions. Doxorubicin- and cisplatin-resistant LUAD cells exhibited elevated SPRTN expression and enhanced rRNA synthesis relative to parental cells. SPRTN knockdown increased apoptotic response to doxorubicin and cisplatin, and co-inhibition of SPRTN and Pol I additively induced apoptosis in both parental and resistant cells. SPRTN further promoted Pol I-dependent migration and invasion. Transcriptomically, SPRTN was upregulated in LUAD, correlated with advanced disease stage and reduced overall survival, and was transcriptionally activated by ZEB1 and post-transcriptionally repressed by miR-195-5p. In vivo, SPRTN silencing reduced tumor burden and suppressed Pol I transcription, with further reduction upon doxorubicin treatment.
CONCLUSION: These findings establish SPRTN as an rDNA-associated repair factor that couples genotoxic damage resolution to Pol I transcriptional resilience, defining the SPRTN-Pol I axis as a determinant of nucleolar homeostasis and therapeutic vulnerability in lung adenocarcinoma.
METHODS: We investigated SPRTN function in LUAD using complementary approaches spanning molecular, cellular, and in vivo levels, including DNA-protein crosslink isolation, chromatin immunoprecipitation, nascent RNA synthesis assays, apoptosis and invasion assays in SPRTN loss- and gain-of-function cell models, mouse xenograft studies, and transcriptomic analysis of clinical LUAD datasets.
RESULTS: SPRTN was enriched at the rDNA promoter, limited basal DPC accumulation, sustained Pol I transcriptional output, suppressed the p53-p21 nucleolar stress checkpoint, and promoted Pol I-dependent proliferation. Under doxorubicin or cisplatin treatment, SPRTN was recruited to G-quadruplex-rich rDNA promoters, a process associated with PARP-1 co-recruitment, and facilitated DPC resolution and transcriptional recovery. Catalytically inactive SPRTN failed to resolve rDNA-DPCs and restore Pol I output under both basal and drug-treated conditions. Doxorubicin- and cisplatin-resistant LUAD cells exhibited elevated SPRTN expression and enhanced rRNA synthesis relative to parental cells. SPRTN knockdown increased apoptotic response to doxorubicin and cisplatin, and co-inhibition of SPRTN and Pol I additively induced apoptosis in both parental and resistant cells. SPRTN further promoted Pol I-dependent migration and invasion. Transcriptomically, SPRTN was upregulated in LUAD, correlated with advanced disease stage and reduced overall survival, and was transcriptionally activated by ZEB1 and post-transcriptionally repressed by miR-195-5p. In vivo, SPRTN silencing reduced tumor burden and suppressed Pol I transcription, with further reduction upon doxorubicin treatment.
CONCLUSION: These findings establish SPRTN as an rDNA-associated repair factor that couples genotoxic damage resolution to Pol I transcriptional resilience, defining the SPRTN-Pol I axis as a determinant of nucleolar homeostasis and therapeutic vulnerability in lung adenocarcinoma.