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J. Biol. Chem., Vol. 279, Issue 47, 49542-49550, November 19, 2004

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The Spindle Pole Body Assembly Component Mps3p/Nep98p Functions in Sister Chromatid Cohesion^*

Lisa M. Antoniacci, Margaret A. Kenna, Peter Uetz¶, Stanley Fields||, and Robert V. Skibbens**

From the Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015, Departments of Genome Sciences and Medicine, University of Washington, Seattle, Washington 98195, and the ^||Departments of Genetics and Medicine, Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195-7360

For successful chromosome segregation during mitosis, several processes must occur early in the cell cycle, including spindle pole duplication, DNA replication, and the establishment of cohesion between nascent sister chromatids. Spindle pole body duplication begins in G₁ and continues during early S-phase as spindle pole bodies mature and start to separate. Key steps in spindle pole body duplication are the sequential recruitment of Cdc31p and Spc42p by the nuclear envelope transmembrane protein Msp3p/Nep98p (herein termed Mps3p). Concurrent with DNA replication, Ctf7p/Eco1p (herein termed Ctf7p) ensures that nascent sister chromatids are paired together, identifying the products of replication as sister chromatids. Here, we provide the first evidence that the nuclear envelope spindle pole body assembly component Mps3p performs a function critical to sister chromatid cohesion. Mps3p was identified as interacting with Ctf7p from a genome-wide two-hybrid screen, and the physical interaction was confirmed by both in vivo (co-immunoprecipitation) and in vitro (GST pull-down) assays. An in vivo cohesion assay on new mps3/nep98 alleles revealed that loss of Mps3p results in precocious sister chromatid separation and that Mps3p functions after G₁, coincident with Ctf7p. Mps3p is not required for cohesion during mitosis, revealing that Mps3p functions in cohesion establishment and not maintenance. Mutated Mps3p that results in cohesion defects no longer binds to Ctf7p in vitro, demonstrating that the interaction between Mps3p and Ctf7p is physiologically relevant. In support of this model, mps3 ctf7 double mutant cells exhibit conditional synthetic lethality. These findings document a new role for Mps3p in sister chromatid cohesion and provide novel insights into the mechanism by which a spindle pole body component, when mutated, contributes to aneuploidy.

Received for publication, April 19, 2004 , and in revised form, September 2, 2004.

^* This material is based upon work supported by National Science Foundation Grant MCB-0212323 (to R. V. S.) and by National Center for Research Resources, National Institutes of Health, Grant P41 RR11823 (to S. F.). 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.

^¶ Present address: Institut fur Genetik, Forschunsgszentrum Karlsruhe, Germany.

^** To whom correspondence should be addressed. Tel.: 610-758-6162; E-mail: rvs3{at}Lehigh.edu.

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