53BP1 and BRCA1 control pathway choice for stalled replication restart
Yixi Xu,
Shaokai Ning,
Zheng Wei,
Ran Xu,
Xinlin Xu,
Mengtan Xing,
Rong Guo,
Dongyi Xu
Affiliations
Yixi Xu
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
Shaokai Ning
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
Zheng Wei
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
Ran Xu
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
Xinlin Xu
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
Mengtan Xing
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
Rong Guo
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
The cellular pathways that restart stalled replication forks are essential for genome stability and tumor prevention. However, how many of these pathways exist in cells and how these pathways are selectively activated remain unclear. Here, we describe two major fork restart pathways, and demonstrate that their selection is governed by 53BP1 and BRCA1, which are known to control the pathway choice to repair double-strand DNA breaks (DSBs). Specifically, 53BP1 promotes a fork cleavage-free pathway, whereas BRCA1 facilitates a break-induced replication (BIR) pathway coupled with SLX-MUS complex-mediated fork cleavage. The defect in the first pathway, but not DSB repair, in a 53BP1 mutant is largely corrected by disrupting BRCA1, and vice versa. Moreover, PLK1 temporally regulates the switch of these two pathways through enhancing the assembly of the SLX-MUS complex. Our results reveal two distinct fork restart pathways, which are antagonistically controlled by 53BP1 and BRCA1 in a DSB repair-independent manner.
