Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
In response to DNA damage and replication blocks, cells prevent cell cycle progression through the control of critical cell cycle regulators. We identified Chk2, the mammalian homolog of the Saccharomyces cerevisiae Rad53 and Schizosaccharomyces pombe Cds1 protein kinases required for the DNA damage and replication checkpoints. Chk2 was rapidly phosphorylated and activated in response to replication blocks and DNA damage; the response to DNA damage occurred in an ataxia telangiectasia mutated (ATM)-dependent manner. In vitro, Chk2 phosphorylated Cdc25C on serine-216, a site known to be involved in negative regulation of Cdc25C. This is the same site phosphorylated by the protein kinase Chk1, which suggests that, in response to DNA damage and DNA replicational stress, Chk1 and Chk2 may phosphorylate Cdc25C to prevent entry into mitosis.
Matsuoka
S
S
Howard Hughes Medical Institute, Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Huang
M
M
Elledge
S J
SJ
D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005720:Gamma Rays; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000254:growth & development; D029702:Schizosaccharomyces pombe Proteins; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D020687:cdc25 Phosphatases
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D029702:Schizosaccharomyces pombe Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; C578636:Cds1 protein, S pombe; D017346:Protein Serine-Threonine Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases