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ATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice

Nicole L Batenburg1, John R Walker1, Sylvie M Noordermeer2,3

  • 1Department of Biology, McMaster University, Hamilton, Ontario, L8S 4K1, Canada.

Nature Communications
|December 6, 2017
PubMed

Insights

Cockayne syndrome group B (CSB) protein recruits to DNA breaks in S phase via interaction with RIF1. CSB

Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Chromatin Remodeling

Background:

  • Cockayne syndrome group B (CSB) is a member of the SWI2/SNF2 superfamily involved in DNA double-strand break (DSB) repair.
  • The precise regulatory mechanisms of CSB in DSB repair remain largely unelucidated.

Purpose of the Study:

  • To investigate the interaction partners and regulatory mechanisms of CSB in DNA double-strand break repair.
  • To elucidate how CSB's chromatin remodeling activity is controlled during the DNA damage response.

Main Methods:

  • Identified a novel winged helix domain in CSB responsible for RIF1 interaction.
  • Investigated CSB recruitment to DSBs in S phase.
  • Assessed CSB's chromatin remodeling activity, including histone eviction and recruitment of repair factors like BRCA1, RIF1, and MAD2L2.
  • Analyzed the role of ATM and cyclin A-CDK2 phosphorylation in modulating CSB activity.

Main Results:

  • CSB interacts with RIF1, an effector of 53BP1, via a newly identified winged helix domain, mediating CSB recruitment to DSBs during S phase.
  • CSB remodels chromatin at DSBs by evicting histones, limiting RIF1/MAD2L2 but promoting BRCA1 accumulation.
  • CSB chromatin remodeling activity is regulated by ATM-mediated phosphorylation at S10 and cyclin A-CDK2-mediated phosphorylation at S158.

Conclusions:

  • CSB's interaction with RIF1 is crucial for its recruitment to DSBs in S phase.
  • CSB's chromatin remodeling function is modulated by ATM and CDK2, influencing DSB repair pathway choice.
  • These findings reveal a novel regulatory pathway for CSB in orchestrating DNA repair.

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