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Adv."],"published-print":{"date-parts":[[2026,10,23]]},"abstract":"<jats:p>\n                    PrimPol-mediated fork repriming generates single-stranded DNA (ssDNA) gaps during DNA damage tolerance (DDT), which, if not properly repaired, can threaten genomic stability. PrimPol is a highly error-prone polymerase. Thus, PrimPol activity should be tightly regulated to fit into DDT and remain low during unstressed DNA replication. Human sex comb on midleg like-2 (SCML2), a Polycomb protein containing MBT repeats, has been identified as a component of the noncanonical PRC1 complex and a regulator of p53 and CHK1 stability. Here, we show that SCML2A is a suppressor of PrimPol. SCML2A directly binds two domains of PrimPol: Its RBR domain binds the C terminus of PrimPol, and its SAM domain binds the amino-terminal AEP domain, thereby inhibiting ssDNA-binding capacity of the AEP domain. SCML2 depletion leads to increased nascent DNA synthesis and accumulation of PrimPol-mediated ssDNA gaps under replication stress. SCML2 depletion also enhances PrimPol engagement during unstressed DNA replication, leading to subsequent accumulation of ssDNA gaps, which are filled by REV1\/POL\u03b6-mediated translesion synthesis (TLS) and RAD51-mediated template switching (TS). SCML2 depletion confers cellular hypersensitivity to RAD51 or REV1\/POL\u03b6 inhibition, which is associated with increased accumulation of ssDNA gaps. Furthermore, CDK2 phosphorylates SCML2A at Ser\n                    <jats:sup>267<\/jats:sup>\n                    , which suppresses RBR-mediated PrimPol interaction. Cyclin E1 overexpression leads to CDK2-mediated SCML2A Ser\n                    <jats:sup>267<\/jats:sup>\n                    hyperphosphorylation, which releases the inhibitory effect of SCML2A on PrimPol and subsequently induces ssDNA gap accumulation. Collectively, we identify SCML2A as a negative regulator of PrimPol.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aee4738","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T17:58:42Z","timestamp":1792778322000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["SCML2 inhibits PrimPol-mediated DNA replication repriming and regulates replication gap-associated cancer cell vulnerability"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2515-5525","authenticated-orcid":true,"given":"Xin","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Peng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2752-5520","authenticated-orcid":true,"given":"Qiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China."},{"name":"Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, China."},{"name":"Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China."},{"name":"Hubei Province Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 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