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Molecular and Cellular Biology, February 2007, p. 1158-1171, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01745-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mitotic Cdc6 Stabilizes Anaphase-Promoting Complex Substrates by a Partially Cdc28-Independent Mechanism, and This Stabilization Is Suppressed by Deletion of Cdc55{triangledown}

Susanna Boronat{dagger} and Judith L. Campbell*

Braun Laboratories 147-75, California Institute of Technology, Pasadena, California 91125

Received 6 September 2006/ Returned for modification 7 October 2006/ Accepted 15 November 2006

Ectopic expression of Cdc6p results in mitotic delay, and this has been attributed to Cdc6p-mediated inhibition of Cdc28 protein kinase and failure to activate the anaphase-promoting complex (APC). Here we show that endogenous Cdc6p delays a specific subset of mitotic events and that Cdc28 inhibition is not sufficient to account for it. The depletion of Cdc6p in G2/M cells reveals that Cdc6p is rate limiting for the degradation of the APC/Cdc20 substrates Pds1p and Clb2p. Conversely, the premature expression of Cdc6p delays the degradation of APC/Cdc20 substrates. Abolishing Cdc6p/Cdc28p interaction does not eliminate the Cdc6-dependent delay of these anaphase events. To identify additional Cdc6-mediated, APC-inhibitory mechanisms, we looked for mutants that reversed the mitotic delay. The deletion of SWE1, RAD24, MAD2, or BUB2 had no effect. However, disrupting CDC55, a PP2A regulatory subunit, suppressed the Cdc6p-dependent delay of Pds1 and Clb2 destruction. A specific role for CDC55 was supported by demonstrating that the lethality of Cdc6 ectopic expression in a cdc16-264 mutant is suppressed by the deletion of CDC55, that endogenous Cdc6p coimmunoprecipitates with the Cdc55 and Tpd3 subunits of PP2A, that Cdc6p/Cdc55p/Tpd3 interaction occurs only during mitosis, and that Cdc6 affects PP2A-Cdc55 activity during anaphase. This demonstrates that the levels and timing of accumulation of Cdc6p in mitosis are appropriate for mediating the modulation of APC/Cdc20.

* Corresponding author. Mailing address: Braun Laboratories 147-75, California Institute of Technology, Pasadena, CA 91125. Phone: (626) 395-6053. Fax: (626) 449-0756. E-mail: jcampbel{at}cco.caltech.edu.

{triangledown} Published ahead of print on 27 November 2006.

{dagger} Present address: Institute of Cellular and Molecular Biology, CSIC, 08034 Barcelona, Spain.

Molecular and Cellular Biology, February 2007, p. 1158-1171, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01745-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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