Cockayne syndrome group B protein regulates DNA double-strand break repair and checkpoint activation

Nicole L. Batenburg, Elizabeth L Thompson, Eric A Hendrickson, Xu Dong Zhu

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Mutations of CSB account for the majority of Cockayne syndrome (CS), a devastating hereditary disorder characterized by physical impairment, neurological degeneration and segmental premature aging. Here we report the generation of a human CSB-knockout cell line. We find that CSB facilitates HR and represses NHEJ. Loss of CSB or a CS-associated CSB mutation abrogating its ATPase activity impairs the recruitment of BRCA1, RPA and Rad51 proteins to damaged chromatin but promotes the formation of 53BP1-Rif1 damage foci in S and G2 cells. Depletion of 53BP1 rescues the formation of BRCA1 damage foci in CSB-knockout cells. In addition, knockout of CSB impairs the ATM- and Chk2-mediated DNA damage responses, promoting a premature entry into mitosis. Furthermore, we show that CSB accumulates at sites of DNA double-strand breaks (DSBs) in a transcription-dependent manner. The kinetics of DSB-induced chromatin association of CSB is distinct from that of its UV-induced chromatin association. These results reveal novel, important functions of CSB in regulating the DNA DSB repair pathway choice as well as G2/M checkpoint activation.

Original languageEnglish (US)
Pages (from-to)1399-1416
Number of pages18
JournalEMBO Journal
Volume34
Issue number10
DOIs
StatePublished - May 12 2015

Bibliographical note

Publisher Copyright:
© 2015 The Authors.

Keywords

  • CSB
  • DNA damage checkpoint
  • DNA double-strand break repair

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