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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\u2010dependent signaling pathways. Finally, we examine emerging roles of PARylation and UFMylation as rapid, replisome\u2010centered regulatory mechanisms that fine\u2010tune fork progression and stability, and we highlight their clinical implications, including a mechanistic link between aberrant replisome regulation and microcephalic primordial dwarfism.<\/jats:p>","DOI":"10.1002\/bies.70185","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:29:37Z","timestamp":1791358177000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Control of Replication Fork Speed: dNTP Availability, Phosphorylation, PARylation, and UFMylation"],"prefix":"10.1002","volume":"48","author":[{"given":"Zheng","family":"Li","sequence":"first","affiliation":[{"name":"Guangdong Key Laboratory for Genome Stability &amp; Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering Shenzhen University Medical School  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Shinohara","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory for Genome Stability &amp; Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering Shenzhen University Medical School  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yisui","family":"Xia","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory for Genome Stability &amp; Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering Shenzhen University Medical School  Shenzhen China"},{"name":"Shenzhen University General Hospital, Shenzhen University Medical School Shenzhen University. Shenzhen  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingzhi","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory for Genome Stability &amp; Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering Shenzhen University Medical School  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunichi","family":"Takeda","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory for Genome Stability &amp; Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering Shenzhen University Medical School  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41586-022-04759-1","article-title":"Fast and Efficient DNA Replication With Purified Human Proteins","volume":"606","author":"Baris Y.","year":"2022","journal-title":"Nature"},{"key":"e_1_2_13_3_1","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature14285","article-title":"Regulated Eukaryotic DNA Replication Origin Firing With Purified Proteins","volume":"519","author":"Yeeles J. 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