Molecular Control of Replication Fork Speed: dNTP Availability, Phosphorylation, PARylation, and UFMylation.

The regulation of replication fork (RF) speed is essential for faithful genome duplication and the maintenance of genome stability, and its dysregulation contributes to carcinogenesis and developmental disorders. Although many anticancer therapies perturb DNA replication, the molecular mechanisms by which RF speed is controlled remain incompletely understood. A major limitation has been the frequent omission of direct measurements of cellular deoxynucleotide triphosphate (dNTP) pools, despite their strong and immediate influence on DNA polymerase kinetics. In this review, we first summarize how dNTP availability constrains RF progression under physiological and stress conditions. We then discuss how anticancer agents targeting DNA replication modulate RF speed through phosphorylation-dependent signaling pathways. Finally, we examine emerging roles of PARylation and UFMylation as rapid, replisome-centered regulatory mechanisms that fine-tune fork progression and stability, and we highlight their clinical implications, including a mechanistic link between aberrant replisome regulation and microcephalic primordial dwarfism.