MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks

Liming Wu, Kuntian Luo, Zhenkun Lou, Junjie Chen

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

The product of the Nijmegen breakage syndrome gene (NBS1) plays crucial roles in DNA damage response through its association with many proteins, including MRE11 and RAD50. However, it remains to be determined exactly how NBS1 accumulates at or near DNA double-strand breaks. Here we report that MDC1 directly binds to NBS1 and targets NBS1 to the sites of DNA damage. The MDC1-NBS1 interaction occurs through a specific region (residues 200-420) of MDC1, which contains multiple consensus casein kinase 2 (CK2) phosphorylation sites. In addition, this interaction requires both the forkhead-associated (FHA) and tandem BRCA1 C-terminal (BRCT) domains of NBS1. Disruption of the MDC1-NBS1 interaction results in failure of NBS1 accumulation at DNA double-strand breaks and impairment of intra-S checkpoint activation. These studies provide important mechanistic insights as to how MDC1 regulates NBS1 and the intra-S-phase checkpoint in response to DNA damage.

Original languageEnglish (US)
Pages (from-to)11200-11205
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number32
DOIs
StatePublished - Aug 12 2008

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S Phase Cell Cycle Checkpoints
Double-Stranded DNA Breaks
DNA Damage
Nijmegen Breakage Syndrome
Casein Kinase II
Phosphorylation
Genes
Proteins

Keywords

  • 53BP1
  • BRCA1
  • Casein kinase 2
  • MRE11

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks. / Wu, Liming; Luo, Kuntian; Lou, Zhenkun; Chen, Junjie.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 32, 12.08.2008, p. 11200-11205.

Research output: Contribution to journalArticle

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