| Cdc6 determines utilization of p21(WAF1/CIP1)-dependent damage checkpoint in S phase cells. | |
MedLine Citation:
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PMID: 18458079 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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When cells traversing G(1) are irradiated with UV light, two parallel damage checkpoint pathways are activated: Chk1-Cdc25A and p53-p21(WAF1/CIP1), both targeting Cdk2, but the latter inducing a long lasting arrest. In similarly treated S phase-progressing cells, however, only the Cdc25A-dependent checkpoint is active. We have recently found that the p21-dependent checkpoint can be activated and induce a prolonged arrest if S phase cells are damaged with a base-modifying agent, such as methyl methanesulfonate (MMS) and cisplatin. But the mechanistic basis for the differential activation of the p21-dependent checkpoint by different DNA damaging agents is not understood. Here we report that treatment of S phase cells with MMS but not a comparable dose of UV light elicits proteasome-mediated degradation of Cdc6, the assembler of pre-replicative complexes, which allows induced p21 to bind Cdk2, thereby extending inactivation of Cdk2 and S phase arrest. Consistently, enforced expression of Cdc6 largely eliminates the prolonged S phase arrest and Cdk2 inactivation induced with MMS, whereas RNA interference-mediated Cdc6 knockdown not only prolongs such arrest and inactivation but also effectively activates the p21-dependent checkpoint in the UV-irradiated S phase cells. |
Authors:
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Qiuming Kan; Shigeki Jinno; Kohei Kobayashi; Hanako Yamamoto; Hiroto Okayama |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-05-05 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 283 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2008 Jun |
Date Detail:
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Created Date: 2008-06-23 Completed Date: 2008-08-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 17864-72 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, University of Tokyo, Tokyo, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Cycle Proteins / metabolism, physiology* Cisplatin / pharmacology Cyclin-Dependent Kinase Inhibitor p21 / metabolism* DNA Damage Humans Methyl Methanesulfonate / pharmacology Mice Models, Biological Nuclear Proteins / metabolism, physiology* RNA Interference S Phase* Ultraviolet Rays cdc25 Phosphatases / metabolism |
| Chemical | |
Reg. No./Substance:
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0/CDC6 protein, human; 0/CDC6 protein, mouse; 0/CDKN1A protein, human; 0/Cdkn1a protein, mouse; 0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Nuclear Proteins; 15663-27-1/Cisplatin; 66-27-3/Methyl Methanesulfonate; EC 3.1.3.16/Cdc25a protein, mouse; EC 3.1.3.48/cdc25 Phosphatases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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