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Molecular and Cellular Biology, December 2009, p. 6500-6514, Vol. 29, No. 24
0270-7306/09/$08.00+0     doi:10.1128/MCB.00669-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cyclin A2-Cyclin-Dependent Kinase 2 Cooperates with the PLK1-SCFβ-TrCP1-EMI1-Anaphase-Promoting Complex/Cyclosome Axis To Promote Genome Reduplication in the Absence of Mitosis {triangledown} ,{dagger}

Hoi Tang Ma, Yiu Huen Tsang, Miriam Marxer, and Randy Y. C. Poon*

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

Received 23 May 2009/ Returned for modification 13 July 2009/ Accepted 6 October 2009

Limiting genome replication to once per cell cycle is vital for maintaining genome stability. Inhibition of cyclin-dependent kinase 1 (CDK1) with the specific inhibitor RO3306 is sufficient to trigger multiple rounds of genome reduplication. We demonstrated that although anaphase-promoting complex/cyclosome (APC/C) remained inactive during the initial G2 arrest, it was activated upon prolonged inhibition of CDK1. Using cellular biosensors and live-cell imaging, we provide direct evidence that genome reduplication was associated with oscillation of APC/C activity and nuclear-cytoplasmic shuttling of CDC6 even in the absence of mitosis at the single-cell level. Genome reduplication was abolished by ectopic expression of EMI1 or depletion of CDC20 or CDH1, suggesting the critical role of the EMI1-APC/C axis. In support of this, degradation of EMI1 itself and genome reduplication were delayed after downregulation of PLK1 and β-TrCP1. In the absence of CDK1 activity, activation of APC/C and genome reduplication was dependent on cyclin A2 and CDK2. Genome reduplication was then promoted by a combination of APC/C-dependent destruction of geminin (thus releasing CDT1), accumulation of cyclin E2-CDK2, and CDC6. Collectively, these results underscore the crucial role of cyclin A2-CDK2 in regulating the PLK1-SCFβ-TrCP1-EMI1-APC/C axis and CDC6 to trigger genome reduplication after the activity of CDK1 is suppressed.

* Corresponding author. Mailing address: Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. Phone: (852) 23588703. Fax: (852) 23581552. E-mail: rycpoon{at}ust.hk

{triangledown} Published ahead of print on 12 October 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2009, p. 6500-6514, Vol. 29, No. 24
0270-7306/09/$08.00+0     doi:10.1128/MCB.00669-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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