Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25.
In response to DNA damage, mammalian cells prevent cell cycle progression through the control of critical cell cycle regulators. A human gene was identified that encodes the protein Chk1, a homolog of the Schizosaccharomyces pombe Chk1 protein kinase, which is required for the DNA damage checkpoint. Human Chk1 protein was modified in response to DNA damage. In vitro Chk1 bound to and phosphorylated the dual-specificity protein phosphatases Cdc25A, Cdc25B, and Cdc25C, which control cell cycle transitions by dephosphorylating cyclin-dependent kinases. Chk1 phosphorylates Cdc25C on serine-216. As shown in an accompanying paper by Peng et al. in this issue, serine-216 phosphorylation creates a binding site for 14-3-3 protein and inhibits function of the phosphatase. These results suggest a model whereby in response to DNA damage, Chk1 phosphorylates and inhibits Cdc25C, thus preventing activation of the Cdc2-cyclin B complex and mitotic entry.
Sanchez
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Verna and Marrs McLean Department of Biochemistry, Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Wong
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C
Thoma
R S
RS
Richman
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R
Wu
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Piwnica-Worms
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Elledge
S J
SJ
D048948:14-3-3 Proteins; D000595:Amino Acid Sequence; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D003598:Cytoskeletal Proteins; D004249:DNA Damage; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D016195:G2 Phase; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins; D015398:Signal Transduction; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; D020687:cdc25 Phosphatases
D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; D011506:Proteins; D011993:Recombinant Fusion Proteins; D029702:Schizosaccharomyces pombe Proteins; C513274:cdc4 protein, S pombe; D010768:Phosphoserine; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605873:Chk1 protein, S pombe; D016203:CDC2 Protein Kinase; D010749:Phosphoprotein Phosphatases; C517004:CDC25A protein, human; C517008:CDC25B protein, human; C517009:CDC25C protein, human; C517005:Cdc25a protein, mouse; C517010:Cdc25c protein, mouse; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases