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J. Biol. Chem., Vol. 282, Issue 24, 17351-17362, June 15, 2007

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Mitotic Phosphorylation of the Anaphase-promoting Complex Inhibitory Subunit Mnd2 Is Necessary for Efficient Progression through Meiosis I^*

Matthew P. Torres and Christoph H. Borchers¹

From the Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, North Carolina 27599 and Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8Z 7X8, Canada

The yeast anaphase-promoting complex (APC) subunit Mnd2 is necessary for maintaining sister chromatid cohesion in prophase I of meiosis by inhibiting premature ubiquitination and subsequent degradation of substrates by the APC^Ama1 ubiquitin ligase. In a proteomics screen for post-translational modifications on the APC, we discovered that Mnd2 is phosphorylated during mitosis in a cell cycle-dependent manner. We identified and characterized the sites of mitotic Mnd2 phosphorylation during the cell cycle. Collective mutation of Mnd2 phosphorylation sites to alanine had no effect on vegetative growth but a striking effect (>85% reduction) on the percentage of tetrad-forming cells compared with the wild type strain. Similar to the MND2 deletion strain, cells harboring the alanine mutant that did not form spores arrested after premeiotic S phase with a single undivided nucleus and low levels of the APC^Ama1 meiotic substrate, Clb5, relative to wild type cells. In contrast, collective mutation of Mnd2 phosphorylation sites to aspartic acid resulted in partial suppression of the sporulation defect. No differences were observed in the binding between each Mnd2 isoform and the APC in vitro. However, in vivo, we observed a gradient in the abundance of APC-associated Mnd2 in each strain that was proportional to the observed differences in sporulation and Clb5 levels. Taken together, these data suggest that mitotic phosphorylation of Mnd2 is necessary for APC-mediated progression beyond the first meiotic nuclear division.

Received for publication, November 24, 2006 , and in revised form, April 13, 2007.

^* This work was funded in part through a Ford Foundation Diversity Fellowship grant (to M. T.) and University of North Carolina startup funds (to C. B.). 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.

¹ To whom correspondence should be addressed: University of Victoria Proteomics Centre, Vancouver Island Technology Park, #3101-4464 Markham St., Victoria, British Columbia V8Z 7X8, Canada. Tel.: 250-483-3221; Fax: 250-483-3238; E-mail: christoph{at}proteincentre.com.

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