SCML2 inhibits PrimPol-mediated DNA replication repriming and regulates replication gap-associated cancer cell vulnerability
5 affiliations
- 1Department of Gastrointestinal Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
- 2State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
- 3Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, China.
- 4Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China.
- 5Hubei Province Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
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.
Related
- PrimPol toggled by ATR modulates fork slowing and repriming under oncogenic KRAS-induced replication stress
- Sodium butyrate inhibits the proliferation of temozolomide-resistant glioblastoma (A172) and lung adenocarcinoma (A549) cells and biphasically regulates EGFR expression
- NEIL2 regulates RNA polymerase II dynamics to suppress transcription replication conflicts in pancreatic cancer
- Quiescence to proliferation transition regulates asynchronous mitochondrial DNA replication dynamics.
- SUMOylation of pseudorabies virus thymidine kinase regulates its nuclear localization and facilitates neuronal replication and reactivation
BibTeX
@article{shi2026scml2,
title = {{SCML2 inhibits PrimPol-mediated DNA replication repriming and regulates replication gap-associated cancer cell vulnerability}},
author = {Xin Shi and Qianqian Peng and Jing Guo and Wei Wu and Ping Wang and Xin Zhou and Qiang Chen},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aee4738},
url = {https://www.science.org/doi/10.1126/sciadv.aee4738},
note = {CC BY},
}
RIS
TY - JOUR
TI - SCML2 inhibits PrimPol-mediated DNA replication repriming and regulates replication gap-associated cancer cell vulnerability
AU - Xin Shi
AU - Qianqian Peng
AU - Jing Guo
AU - Wei Wu
AU - Ping Wang
AU - Xin Zhou
AU - Qiang Chen
PY - 2026
DA - 2026/10/23
JO - Science Advances
DO - 10.1126/sciadv.aee4738
UR - https://www.science.org/doi/10.1126/sciadv.aee4738
AB - 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.
SN - 2375-2548
ER -