期刊
CELL CYCLE
卷 13, 期 7, 页码 1078-1090出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.27946
关键词
Mre11; Xrs2; cyclin-dependent kinase; DNA repair; mitosis
类别
资金
- Canadian Institutes of Health Research (CIHR) [MOP 82912]
- Cancer Research Society (CRS)
- Canadian Cancer Society Research Institute (CCSRI) [020304]
- Tier II Canada Research Chair in Cell Cycle Regulation and Genomic Integrity
- Cole Foundation
- CIHR
- FRSQ
Homologous recombination (HR) and non-homologous end joining (NHEJ) are the main pathways ensuring the repair of DNA double-stranded breaks (DSBs) in eukaryotes. It has long been known that cell cycle stage is a major determinant of the type of pathway used to repair DSBs in vivo. However, the mechanistic basis for the cell cycle regulation of the DNA damage response is still unclear. Here we show that a major DSB sensor, the Mre11-Rad50-Xrs2 (MRX) complex, is regulated by cell cycle-dependent phosphorylation specifically in mitosis. This modification depends on the cyclin-dependent kinase Cdc28/Cdk1, and abrogation of Xrs2 and Mre11 phosphorylation results in a marked preference for DSB repair through NHEJ. Importantly, we show that phosphorylation of the MRX complex after DNA damage and during mitosis are regulated independently of each other by Tel1/ATM and Cdc28/Cdk1 kinases. Collectively, our results unravel an intricate network of phosphoregulatory mechanisms that act through the MRX complex to modulate DSB repair efficiency during mitosis.
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