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EMBO J. 2010 Sep 1;29(17):2966-78. doi: 10.1038/emboj.2010.171. Epub 2010 Jul 23.

IKK and NF-kappaB-mediated regulation of Claspin impacts on ATR checkpoint function.

Author information

  • 1Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.

Erratum in

  • EMBO J. 2012 May 30;31(11):2660-1.

Abstract

In response to replication stress, Claspin mediates the phosphorylation and activation of Chk1 by ATR. Claspin is not only necessary for the propagation of the DNA-damage signal, but its destruction by the ubiquitin-proteosome pathway is required to allow the cell to continue the cell cycle allowing checkpoint recovery. Here, we demonstrate that both the NF-kappaB family of transcription factors and their upstream kinase IKK can regulate Claspin levels by controlling its mRNA expression. Furthermore, we show that c-Rel directly controls Claspin gene transcription. Disruption of IKK and specific NF-kappaB members impairs ATR-mediated checkpoint function following DNA damage. Importantly, hyperactivation of IKK results in a failure to inactivate Chk1 and impairs the recovery from the DNA checkpoint. These results uncover a novel function for IKK and NF-kappaB modulating the DNA-damage checkpoint response, allowing the cell to integrate different signalling pathways with the DNA-damage response.

PMID:
20657549
[PubMed - indexed for MEDLINE]
PMCID:
PMC2944043
Free PMC Article
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