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Molecular and Cellular Biology, December 2006, p. 9162-9176, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.00603-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Acm1 Is a Negative Regulator of the Cdh1-Dependent Anaphase-Promoting Complex/Cyclosome in Budding Yeast ^{, ,}

Juan S. Martinez,^3, Dah-Eun Jeong,^3, Eunyoung Choi,³ Brian M. Billings,³ and Mark C. Hall^1,2,3*

Purdue Cancer Center,¹ Bindley Bioscience Center,² Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907³

Received 7 April 2006/ Returned for modification 24 May 2006/ Accepted 25 September 2006

Cdh1 is a coactivator of the anaphase-promoting complex/cyclosome (APC/C) and contributes to mitotic exit and G₁ maintenance by facilitating the polyubiquitination and subsequent proteolysis of specific substrates. Here, we report that budding yeast Cdh1 is a component of a cell cycle-regulated complex that includes the 14-3-3 homologs Bmh1 and Bmh2 and a previously uncharacterized protein, which we name Acm1 (APC/C^Cdh1 modulator 1). Association of Cdh1 with Bmh1 and Bmh2 requires Acm1, and the Acm1 protein is cell cycle regulated, appearing late in G₁ and disappearing in late M. In acm1 strains, Cdh1 localization to the bud neck and association with two substrates, Clb2 and Hsl1, were strongly enhanced. Several lines of evidence suggest that Acm1 can suppress APC/C^Cdh1-mediated proteolysis of mitotic cyclins. First, overexpression of Acm1 fully restored viability to cells expressing toxic levels of Cdh1 or a constitutively active Cdh1 mutant lacking inhibitory phosphorylation sites. Second, overexpression of Acm1 was toxic in sic1 cells. Third, ACM1 deletion exacerbated a low-penetrance elongated-bud phenotype caused by modest overexpression of Cdh1. This bud elongation was independent of the morphogenesis checkpoint, and the combination of acm1 and hsl1 resulted in a dramatic enhancement of bud elongation and G₂/M delay. Effects on bud elongation were attenuated when Cdh1 was replaced with a mutant lacking the C-terminal IR dipeptide, suggesting that APC/C-dependent proteolysis is required for this phenotype. We propose that Acm1 and Bmh1/Bmh2 constitute a specialized inhibitor of APC/C^Cdh1.

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* Corresponding author. Mailing address: 175 S. University St., West Lafayette, IN 47907. Phone: (765) 494-0714. Fax: (765) 494-7897. E-mail: mchall{at}purdue.edu.

Published ahead of print on 9 October 2006.

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

Journal paper 17975 from the Purdue University Agricultural Experiment Station.

J.S.M. and D.-E.J. contributed equally to this work.

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Molecular and Cellular Biology, December 2006, p. 9162-9176, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.00603-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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