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

The EMBO Journal
Niall Steven KennethSonia Rocha

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.

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Citations

Jan 20, 2012·Nature Reviews. Cancer·Neil D Perkins
Feb 8, 2011·PLoS Genetics·Patrick van UdenSonia Rocha
Jan 13, 2016·British Journal of Cancer·Jill E HunterNeil D Perkins
Mar 13, 2012·The International Journal of Biochemistry & Cell Biology·Nicola FullardFiona Oakley
Sep 29, 2012·The Biochemical Journal·Niall S KennethSonia Rocha
Apr 2, 2016·The Journal of Investigative Dermatology·Verena N LorenzCornelia S Seitz
Jun 23, 2018·The FEBS Journal·Veronique A J SmitsDavid A Gillespie
May 23, 2018·The Biochemical Journal·John BiddlestoneSonia Rocha
Dec 9, 2015·Journal of Cell Science·Brian OrtmannSonia Rocha
Dec 17, 2014·Disease Models & Mechanisms·Daniel BandarraSonia Rocha

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