ATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice.
Nicole L BatenburgJohn R WalkerSylvie M NoordermeerNathalie MoattiDaniel DurocherXu-Dong ZhuPublished in: Nature communications (2017)
CSB, a member of the SWI2/SNF2 superfamily, is implicated in DNA double-strand break (DSB) repair. However, how it regulates this repair process is poorly understood. Here we uncover that CSB interacts via its newly identified winged helix domain with RIF1, an effector of 53BP1, and that this interaction mediates CSB recruitment to DSBs in S phase. At DSBs, CSB remodels chromatin by evicting histones, which limits RIF1 and its effector MAD2L2 but promotes BRCA1 accumulation. The chromatin remodeling activity of CSB requires not only damage-induced phosphorylation on S10 by ATM but also cell cycle-dependent phosphorylation on S158 by cyclin A-CDK2. Both modifications modulate the interaction of the CSB N-terminal region with its ATPase domain, the activity of which has been previously reported to be autorepressed by the N-terminal region. These results suggest that ATM and CDK2 control the chromatin remodeling activity of CSB in the regulation of DSB repair pathway choice.
Keyphrases
- cell cycle
- dna damage
- cell proliferation
- gene expression
- transcription factor
- dna repair
- genome wide
- pulmonary tuberculosis
- oxidative stress
- dna damage response
- dendritic cells
- regulatory t cells
- dna methylation
- mycobacterium tuberculosis
- signaling pathway
- protein kinase
- decision making
- drug induced
- endothelial cells
- circulating tumor
- high glucose
- dna binding
- type iii