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J. Biol. Chem., Vol. 282, Issue 47, 34176-34184, November 23, 2007

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The Yeast Hex3·Slx8 Heterodimer Is a Ubiquitin Ligase Stimulated by Substrate Sumoylation^*

Yang Xie¹, Oliver Kerscher¹², Mary B. Kroetz^¶, Heather F. McConchie³, Patrick Sung, and Mark Hochstrasser⁴

From the Department of Molecular Biophysics and Biochemistry and ^¶Department of Cell Biology, Yale University New Haven, Connecticut 06520-8114 and Department of Biology, College of William and Mary, Williamsburg, Virginia 23185

Hex3 and Slx8 are Saccharomyces cerevisiae proteins with important functions in DNA damage control and maintenance of genomic stability. Both proteins have RING domains at their C termini. Such domains are common in ubiquitin and ubiquitin-like protein ligases (E3s), but little was known about the molecular functions of either protein. In this study we identified HEX3 as a high-copy suppressor of a temperature-sensitive small ubiquitin-related modifier (SUMO) protease mutant, ulp1ts, suggesting that it may affect cellular SUMO dynamics. Remarkably, even a complete deletion of ULP1 is strongly suppressed. Hex3 forms a heterodimer with Slx8. We found that the Hex3·Slx8 complex has a robust substrate-specific E3 ubiquitin ligase activity. In this E3 complex, Slx8 appears to bear the core ligase function, with Hex3 strongly enhancing its activity. Notably, SUMO attachment to a substrate stimulates its Hex3·Slx8-dependent ubiquitination, primarily through direct noncovalent interactions between SUMO and Hex3. Our data reveal a novel mechanism of substrate targeting in which sumoylation of a protein can help trigger its subsequent ubiquitination by recruiting a SUMO-binding ubiquitin ligase.

Received for publication, July 23, 2007 , and in revised form, September 4, 2007.

^* This study was funded by National Institutes of Health Grants GM053756 and GM046904 (to M. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ These authors contributed equally.

² Supported by the College of William and Mary and the Christopher Wren Society.

³ Supported by the William and Mary undergraduate Science Education and Research Program sponsored by the Howards Hughes Medical Institute.

⁴ To whom correspondence should be addressed: Dept. of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Ave., New Haven, CT 06520-8114. Tel.: 203-432-6507; Fax: 203-432-5158; E-mail: mark.hochstrasser{at}yale.edu.

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