Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage.
DNA damage causes stabilization of p53, leading to G1 arrest through induction of p21cip1. As this process requires transcription, several hours are needed to exert this response. We show that DNA damage causes an immediate and p53-independent G1 arrest, caused by rapid proteolysis of cyclin D1. Degradation is mediated through a previously unrecognized destruction box in cyclin D1 and leads to a release of p21cip1 from CDK4 to inhibit CDK2. Interference with cyclin D1 degradation prevents initiation of G1 arrest and renders cells more susceptible to DNA damage, indicating that cyclin D1 degradation is an essential component of the cellular response to genotoxic stress. Thus, induction of G1 arrest in response to DNA damage is minimally a two step process: a fast p53-independent initiation of G1 arrest mediated by cyclin D1 proteolysis and a slower maintenance of arrest resulting from increased p53 stability.
Agami
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R
Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam.
Bernards
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R
D020816:Amino Acid Motifs; D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D002945:Cisplatin / Q000494:pharmacology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004249:DNA Damage; D016193:G1 Phase; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011817:Rabbits; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007976:Leupeptins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011518:Proto-Oncogene Proteins; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; C098734:carbobenzoxy-leucyl-leucyl-leucine; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin