IKK and NF-kappa B-mediated regulation of Claspin impacts on ATR checkpoint function

TY - JOUR

T1 - IKK and NF-kappa B-mediated regulation of Claspin impacts on ATR checkpoint function

AU - Kenneth,Niall Steven

AU - Mudie,Sharon

AU - Rocha,Sonia

PY - 2010/9/1

Y1 - 2010/9/1

N2 - 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-kappa B 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-kappa B 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-kappa B modulating the DNA-damage checkpoint response, allowing the cell to integrate different signalling pathways with the DNA-damage response. The EMBO Journal (2010) 29, 2966-2978. doi: 10.1038/emboj.2010.171; Published online 23 July 2010

AB - 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-kappa B 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-kappa B 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-kappa B modulating the DNA-damage checkpoint response, allowing the cell to integrate different signalling pathways with the DNA-damage response. The EMBO Journal (2010) 29, 2966-2978. doi: 10.1038/emboj.2010.171; Published online 23 July 2010

KW - Chk1

KW - Claspin

KW - IKK

KW - NF-kappa B

KW - CELL-CYCLE

KW - CHK1 ACTIVATION

KW - GENE-EXPRESSION

KW - BREAST-CANCER

KW - DEGRADATION

KW - RECOVERY

KW - PHOSPHORYLATION

KW - DOWNSTREAM

KW - INHIBITION

KW - PATHWAYS

U2 - 10.1038/emboj.2010.171

DO - 10.1038/emboj.2010.171

M3 - Article

VL - 29

SP - 2966

EP - 2978

JO - EMBO Journal

T2 - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 17

ER -