IKK and NF-kappaB-mediated regulation of Claspin impacts on ATR checkpoint function.
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.
Kenneth
Niall Steven
NS
Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
Mudie
Sharon
S
Rocha
Sonia
S
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D055786:Gene Knockout Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D016254:Mutagenesis, Insertional; D016328:NF-kappa B / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D015398:Signal Transduction; D014161:Transduction, Genetic
D048868:Adaptor Proteins, Signal Transducing; C488158:CLSPN protein, human; D018797:Cell Cycle Proteins; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase