Document Detail

Cdc6 determines utilization of p21(WAF1/CIP1)-dependent damage checkpoint in S phase cells.
MedLine Citation:
PMID:  18458079     Owner:  NLM     Status:  MEDLINE    
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.
Qiuming Kan; Shigeki Jinno; Kohei Kobayashi; Hanako Yamamoto; Hiroto Okayama
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-05-05
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-06-23     Completed Date:  2008-08-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17864-72     Citation Subset:  IM    
Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
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MeSH Terms
Cell Cycle Proteins / metabolism,  physiology*
Cisplatin / pharmacology
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
DNA Damage
Methyl Methanesulfonate / pharmacology
Models, Biological
Nuclear Proteins / metabolism,  physiology*
RNA Interference
S Phase*
Ultraviolet Rays
cdc25 Phosphatases / metabolism
Reg. No./Substance:
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 protein, mouse; EC Phosphatases

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