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Nucleic Acids Res. 2019 Nov 18;47(20):10678-10692. doi: 10.1093/nar/gkz784.

CSB interacts with BRCA1 in late S/G2 to promote MRN- and CtIP-mediated DNA end resection.

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Department of Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Division, 9 McMahon, Québec City, QC G1R 3S3, Canada.
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, QC G1V 0A6, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada.


CSB, a member of the SWI2/SNF2 superfamily, has been implicated in evicting histones to promote the DSB pathway choice towards homologous recombination (HR) repair. However, how CSB promotes HR repair remains poorly characterized. Here we demonstrate that CSB interacts with both MRE11/RAD50/NBS1 (MRN) and BRCA1 in a cell cycle regulated manner, with the former requiring its WHD and occurring predominantly in early S phase. CSB interacts with the BRCT domain of BRCA1 and this interaction is regulated by CDK-dependent phosphorylation of CSB on S1276. The CSB-BRCA1 interaction, which peaks in late S/G2 phase, is responsible for mediating the interaction of CSB with the BRCA1-C complex consisting of BRCA1, MRN and CtIP. While dispensable for histone eviction at DSBs, CSB phosphorylation on S1276 is necessary to promote efficient MRN- and CtIP-mediated DNA end resection, thereby restricting NHEJ and enforcing the DSB repair pathway choice to HR. CSB phosphorylation on S1276 is also necessary to support cell survival in response to DNA damage-inducing agents. These results altogether suggest that CSB interacts with BRCA1 to promote DNA end resection for HR repair and that although prerequisite, CSB-mediated histone eviction alone is insufficient to promote the pathway choice towards HR.

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