Phosphorylation of RNF213 by ATM-mediated ubiquitination of RPA1 regulates homologous recombination repair and chemosensitivity

Replication protein A1 (RPA1) is a crucial regulator of homologous recombination (HR) repair and DNA end resection. Studies have demonstrated that the expression and activity of RPA1 are regulated through posttranslational modifications. However, the exact molecular mechanism through which RPA1 activity is regulated remains unclear. Here, we discovered that RNF213 interacts directly with and ubiquitinates RPA1, thereby inhibiting HR repair and DNA end resection. Furthermore, RNF213 is phosphorylated by ATM at Ser217 following DNA damage, which increases the catalytic activity of RNF213. In addition, RNF213 overexpression sensitizes triple-negative breast cancer (TNBC) cells to PARP inhibitor (PARPi) treatment in an RPA1-dependent manner both in vitro and in vivo. Taken together, our findings reveal that RNF213 modulates the response of TNBC cells to PARPi treatment by regulating the ubiquitination of RPA1 and inhibiting HR repair.

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Publication Details

Journal
Cell Death and Disease
Published
2025-10-21
DOI
https://doi.org/10.1038/s41419-025-08041-w
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

Phosphorylation of RNF213 by ATM-mediated ubiquitination of RPA1 regulates homologous recombination repair and chemosensitivity

Zhiwang Song, Bin Ruan, Dingwen Hu, Chun‐Te Wu et al.
Cell Death and Disease
DNA Repair Mechanisms
article

Phosphorylation of RNF213 by ATM-mediated ubiquitination of RPA1 regulates homologous recombination repair and chemosensitivity

Zhiwang Song, Bin Ruan, Dingwen Hu, Chun‐Te Wu, Jun Li, Yili Wang, Wenli Wu, Yanxia Jiang, Heng Cheng
article en

Abstract

Replication protein A1 (RPA1) is a crucial regulator of homologous recombination (HR) repair and DNA end resection. Studies have demonstrated that the expression and activity of RPA1 are regulated through posttranslational modifications. However, the exact molecular mechanism through which RPA1 activity is regulated remains unclear. Here, we discovered that RNF213 interacts directly with and ubiquitinates RPA1, thereby inhibiting HR repair and DNA end resection. Furthermore, RNF213 is phosphorylated by ATM at Ser217 following DNA damage, which increases the catalytic activity of RNF213. In addition, RNF213 overexpression sensitizes triple-negative breast cancer (TNBC) cells to PARP inhibitor (PARPi) treatment in an RPA1-dependent manner both in vitro and in vivo. Taken together, our findings reveal that RNF213 modulates the response of TNBC cells to PARPi treatment by regulating the ubiquitination of RPA1 and inhibiting HR repair.

Cell Death and DiseaseVol. 16(1)
Mayo Clinic (US), Nanchang University (CN), Shanghai Jiao Tong University (CN), First Affiliated Hospital of Jiangxi Medical College (CN), Tongren Hospital (CN), Hainan Modern Women and Children's Hospital (CN), Third Hospital of Nanchang (CN), Mayo Clinic in Arizona (US), Mayo Clinic in Florida (US), Hainan Medical College Hospital (CN), First Affiliated Hospital of Nanchang University (CN), Hainan Medical University (CN)
National Natural Science Foundation of China
Openalex Percentile: Top 73%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
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