A Study of "A PARylation-phosphorylation cascade dictates TOPBP1 loading and RPA-RAD51 exchange in homologous recombination". Jiao Zhao et al
Description
Homologous recombination (HR) is a high-fidelity, template-dependent repair pathway of DNA double-strand breaks (DSBs). The integrity of HR system is tightly associated with genome stability and tumor response to chemotherapy. Yet, how HR activity is regulated remains to be investigated. Here, we report that the RNA binding protein HTATSF1 is highly expressed in S phase and is physically associated with Topoisomerase II-binding protein 1 (TOPBP1) in a cell-cycle and phosphorylation dependent manner. Specifically, HTATSF1 is phosphorylated by CK2 kinase at Ser748 and the phosphorylation mark is read by the N-terminal BRCA1 C-terminal (BRCT) domains of TOPBP1. The HTATSF1-TOPBP1 binding primarily promotes S-phase TOPBP1 recruitment, but the transcriptional activity of HTATSF1 is not involved in TOPBP1-associated DNA damage response. Importantly, the RNA recognition motifs (RRMs) of HTATSF1 interact with poly(ADP-ribosyl)ated RPA, and this allows the engagement of HTATSF1-TOPBP1 complex to post-resected DSB ends and facilitates the exchange of RPA and RAD51 to favor HR repair of DSBs. Together, our study provides mechanistic insight into TOPBP1 loading at HR-prone DSB sites, and reveals how RPA-RAD51 exchange is tuned by a HTATSF1-TOPBP1 complex nucleated PARylation-phosphorylation writing and reading cascade. Raw data for “A PARylation-phosphorylation cascade dictates TOPBP1 loading and RPA-RAD51 exchange in homologous recombination” is presented here.