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J. Biol. Chem., Vol. 283, Issue 23, 15716-15723, June 6, 2008

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The Kinetics of p53 Activation Versus Cyclin E Accumulation Underlies the Relationship between the Spindle-assembly Checkpoint and the Postmitotic Checkpoint^*

From the Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong

Although cells can exit mitotic block aberrantly by mitotic slippage, they are prevented from becoming tetraploids by a p53-dependent postmitotic checkpoint. Intriguingly, disruption of the spindle-assembly checkpoint also compromises the postmitotic checkpoint. The precise mechanism of the interplay between these two pivotal checkpoints is not known. We found that after prolonged nocodazole exposure, the postmitotic checkpoint was facilitated by p53. We demonstrated that although disruption of the mitotic block by a MAD2-binding protein promoted slippage, it did not influence the activation of p53. Both p53 and its downstream target p21^CIP1/WAF1 were activated at the same rate irrespective of whether the spindle-assembly checkpoint was enforced or not. The accelerated S phase entry, as reflected by the premature accumulation of cyclin E relative to the activation of p21^CIP1/WAF1, is the reason for the uncoupling of the postmitotic checkpoint. In support of this hypothesis, forced premature mitotic exit with a specific CDK1 inhibitor triggered DNA replication without affecting the kinetics of p53 activation. Finally, replication after checkpoint bypass was boosted by elevating the level of cyclin E. These observations indicate that disruption of the spindle-assembly checkpoint does not directly influence p53 activation, but the shortening of the mitotic arrest allows cyclin E-CDK2 to be activated before the accumulation of p21^CIP1/WAF1. These data underscore the critical relationship between the spindle-assembly checkpoint and the postmitotic checkpoint in safeguarding chromosomal stability.

Received for publication, January 24, 2008 , and in revised form, April 4, 2008.

^* This work was supported in part by Research Grants Council Grants HKUST6123/04M, HKUST6415/05M, and HKUST6439/06 M (to R. Y. C. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S7.

¹ Recipient of a DuPont scholarship. Present address: Dept. of Cell Biology, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany.

² To whom correspondence should be addressed: Dept. of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. Tel.: 852-23588703; Fax: 852-23581552; E-mail: rycpoon{at}ust.hk.

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