Cdc6 Determines Utilization of p21WAF1/CIP1-dependent Damage Checkpoint in S Phase Cells.

Cdc6 Determines Utilization of p21WAF1/CIP1-dependent Damage Checkpoint in S Phase Cells. Research Abstract Details 

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Cdc6 Determines Utilization of p21WAF1/CIP1-dependent Damage Checkpoint in S Phase Cells. Abstract Text:

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.

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Cdc6 Determines Utilization of p21WAF1/CIP1-dependent Damage Checkpoint in S Phase Cells. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The Journal of biological chemistry

VOLUME: 283

Page Numbers: 17864-72

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 5

MONTH: 05

YEAR: 2008

Cdc6 Determines Utilization of p21WAF1/CIP1-dependent Damage Checkpoint in S Phase Cells. Information

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LANGUAGE: eng

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AFFILIATION: Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.

Country: United States

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MEDLINETA: J Biol Chem

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