IKK and NF-kappa B-mediated regulation of Claspin impacts on ATR checkpoint function. / Kenneth, Niall Steven; Mudie, Sharon; Rocha, Sonia.
In: EMBO Journal, Vol. 29, No. 17, 01.09.2010, p. 2966-2978.Research output: Contribution to journal › Article
}
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 -