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J. Biol. Chem., Vol. 281, Issue 27, 18414-18425, July 7, 2006

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A Conserved Hsp10-like Domain in Mcm10 Is Required to Stabilize the Catalytic Subunit of DNA Polymerase- in Budding Yeast^*

From the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455

Mcm10 is a conserved eukaryotic DNA replication factor that is required for S phase progression. Recently, Mcm10 has been shown to interact physically with the DNA polymerase- (pol-)·primase complex. We show now that Mcm10 is in a complex with pol- throughout the cell cycle. In temperature-sensitive mcm10-1 mutants, depletion of Mcm10 results in degradation of the catalytic subunit of pol-, Cdc17/Pol1, regardless of whether cells are in G₁, S, or G₂ phase. Importantly, Cdc17 protein levels can be restored upon overexpression of exogenous Mcm10 in mcm10-1 mutants that are grown at the nonpermissive temperature. Moreover, overexpressed Cdc17 that is normally subject to rapid degradation is stabilized by Mcm10 co-overexpression but not by co-overexpression of the B-subunit of pol-, Pol12. These results are consistent with Mcm10 having a role as a nuclear chaperone for Cdc17. Mutational analysis indicates that a conserved heat-shock protein 10 (Hsp10)-like domain in Mcm10 is required to prevent the degradation of Cdc17. Substitution of a single residue in the Hsp10-like domain of endogenous Mcm10 results in a dramatic reduction of steady-state Cdc17 levels. The high degree of evolutionary conservation of this domain implies that stabilizing Cdc17 may be a conserved function of Mcm10.

Received for publication, December 21, 2005 , and in revised form, April 18, 2006.

^* This work was supported by National Institutes of Health Grant GM074917 (to A.-K. 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: Dept. of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455. Tel.: 612-624-2469; Fax: 612-625-2163; E-mail: bielinsk{at}cbs.umn.edu.

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