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.