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J. Biol. Chem., Vol. 279, Issue 26, 26830-26838, June 25, 2004

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Sir Antagonist 1 (San1) Is a Ubiquitin Ligase^*

Arindam Dasgupta, Kerrington L. Ramsey, Jeffrey S. Smith, and David T. Auble

From the Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, Virginia 22908-0733

Mutations in Sir Antagonist 1 (SAN1) suppress defects in SIR4 and SPT16 in Saccharomyces cerevisiae. San1 contains a RING domain, suggesting that it functions by targeting mutant sir4 and spt16 proteins for degradation by a ubiquitin-mediated pathway. Consistent with this idea, mutant sir4 and spt16 proteins are unstable in SAN1 cells but are stabilized in san1 cells. We demonstrate that San1 possesses ubiquitin-protein isopeptide ligase activity in vitro, and the ubiquitin-protein isopeptide ligase activity of San1 is required for its function in vivo. Wild-type Sir4 has a half-life of about 21 min, and san1 increased Sir4 half-life to >90 min. In contrast, san1 did not affect the stability of wild-type Spt16, Sir3, Sir2, or the Spt16-associated proteins Pob3 and Nhp6. Loss of SAN1 also did not affect the stability of Ste6-166, a highly unstable protein in yeast. These results support the idea that San1 controls the turnover of a specific class of unstable nuclear proteins. Sir4 nucleates the assembly of silent chromatin at telomeres and the silent mating-type loci (HM) in S. cerevisiae. Sir4 can also affect silencing in the rDNA indirectly by sequestering limiting Sir2. Increasing the stability of wild-type Sir4 by deleting SAN1 had only subtle effects on silencing, suggesting that silent chromatin in yeast is robustly buffered against changes in Sir4 stability. Consistent with the idea that San1 participates as an accessory factor to regulate silent chromatin, including the silent mating-type loci, microarray analysis defined a small but statistically significant role for San1 in transcription of several mating pheromone-responsive genes.

Received for publication, January 27, 2004 , and in revised form, April 9, 2004.

^* This work was supported by National Institutes of Health Grant GM55763 (to D. T. A.), The March of Dimes, The Kincaid Charitable Trust, National Institutes of Health Grant GM61692 (to J. S. S.), and University of Virginia Cancer Center Support Grant P30-CA44579. 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.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, University of Virginia Health System, 1300 Jefferson Park Ave., Rm. 6213, Charlottesville, VA 22908-0733. Tel.: 434-243-2629; Fax: 434-924-5069; E-mail: dta4n{at}virginia.edu.

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