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- Title
IKK and NF-kappaB-mediated regulation of Claspin impacts on ATR checkpoint function.
- Authors
Kenneth, Niall Steven; Mudie, Sharon; Rocha, Sonia
- 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.
- Publication
The EMBO journal, 2010, Vol 29, Issue 17, p2966
- ISSN
1460-2075
- Publication type
Journal Article
- DOI
10.1038/emboj.2010.171