Spreading the signal: dissociation of Chk1 from chromatin.
The effector kinase Chk1 plays a critical role in the DNA damage checkpoint response by phosphorylating regulators of the cell cycle machinery, resulting in an inhibition of cell cycle progression. In the presence of genotoxic stress, the PI3 kinase-like kinase ATR rapidly phosphorylates Chk1 on conserved serine residues, thereby triggering kinase activation through the release of an auto-inhibitory region present at its C-terminus and by regulating interactions with other proteins. Recent data have demonstrated an additional regulatory mechanism of Chk1 functioning: Chk1 binds chromatin in unperturbed cells and dissociates from chromatin in response to DNA damage in a manner that is dependent on PIKK-mediated phosphorylation. Here, I give an overview of these findings and discuss the implications of these data for our understanding of the execution of the checkpoint arrest induced after the detection of DNA damage.
Smits
Veronique A J
VA
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. v.a.j.smits@erasmusmc.nl
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases