{
  "abstract": "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/POLζ-mediated translesion synthesis (TLS) and RAD51-mediated template switching (TS). SCML2 depletion confers cellular hypersensitivity to RAD51 or REV1/POLζ inhibition, which is associated with increased accumulation of ssDNA gaps. Furthermore, CDK2 phosphorylates SCML2A at Ser²⁶⁷, which suppresses RBR-mediated PrimPol interaction. Cyclin E1 overexpression leads to CDK2-mediated SCML2A Ser²⁶⁷ 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Gastrointestinal Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.",
    "State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.",
    "Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, China.",
    "Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China.",
    "Hubei Province Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xin Shi",
      "orcid": "0009-0000-2515-5525"
    },
    {
      "affs": [
        1
      ],
      "name": "Qianqian Peng"
    },
    {
      "affs": [
        0
      ],
      "name": "Jing Guo"
    },
    {
      "affs": [
        0
      ],
      "name": "Wei Wu"
    },
    {
      "affs": [
        0
      ],
      "name": "Ping Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xin Zhou"
    },
    {
      "affs": [
        0,
        2,
        3,
        4
      ],
      "name": "Qiang Chen",
      "orcid": "0000-0003-2752-5520"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1ktpx24fm4x22.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aee4738",
  "fulltext_url": "https://europepmc.org/articles/PMC13693694",
  "id": "1ktpx24fm4x22",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aee4738",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|DNA Repair Mechanisms"
    ]
  ],
  "openalex": "W7223363522",
  "pdf_url": "https://europepmc.org/articles/PMC13693694?pdf=render",
  "pmcid": "PMC13693694",
  "pmid": "42913014",
  "published": "2026-10-23",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/1ktpx24fm4x22.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aee4738",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aee4738"
    },
    {
      "first_seen": "2026-10-30T12:20:03Z",
      "native_id": "MED:42913014",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42913014"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|DNA Repair Mechanisms",
      "subfield": "molecular-biology"
    }
  ],
  "title": "SCML2 inhibits PrimPol-mediated DNA replication repriming and regulates replication gap-associated cancer cell vulnerability",
  "title_text": "SCML2 inhibits PrimPol-mediated DNA replication repriming and regulates replication gap-associated cancer cell vulnerability",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:03Z",
  "url": "https://research.draconitic.com/paper/1ktpx24fm4x22",
  "venue": "Science Advances",
  "versions": []
}