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J. Biol. Chem., Vol. 281, Issue 17, 11744-11754, April 28, 2006

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Determinants of the Ubiquitin-mediated Degradation of the Met4 Transcription Factor^*

Alexandra Menant¹, Peggy Baudouin-Cornu², Caroline Peyraud³, Mike Tyers⁴, and Dominique Thomas^¶5

From the Centre de Génétique Moléculaire, Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvettte, France, ^¶Cytomics Systems SA, Btiment 5, 1 Avenue de la Terrasse, 91190 Gif-sur-Yvette, France, and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5

In yeast, the Met4 transcription factor and its cofactors Cbf1, Met28, Met31, and Met32 control the expression of sulfur metabolism and oxidative stress response genes. Met4 activity is tuned to nutrient and oxidative stress conditions by the SCF^Met30 ubiquitin ligase. The mechanism whereby SCF^Met30-dependent ubiquitylation of Met4 controls Met4 activity remains contentious. Here, we have demonstrated that intracellular cysteine levels dictate the degradation of Met4 in vivo, as shown by the ability of cysteine, but not methionine or S-adenosylmethionine (AdoMet), to trigger Met4 degradation in an str4 strain, which lacks the ability to produce cysteine from methionine or AdoMet. Met4 degradation requires its nuclear localization and activity of the 26 S proteasome. Analysis of the regulated degradation of a fully functional Met4-Cbf1 chimera, in which Met4 is fused to the DNA binding domain of Cbf1, demonstrates that elimination of Met4 in vivo can be triggered independently of both its normal protein interactions. Strains that harbor the Met4-Cbf1 fusion as the only source of Cbf1 activity needed for proper kinetochore function exhibit high rates of methionine-dependent chromosomal instability. We suggest that SCF^Met30 activity or Met4 utilization as a substrate may be directly regulated by intracellular cysteine concentrations.

Received for publication, January 3, 2006 , and in revised form, February 23, 2006.

^* This work was supported in part by funds from the Centre National de la Recherche Scientifique and the Association de la Recherche sur le Cancer (to D. T.) and by grants from the National Cancer Institute of Canada and the Canadian Institutes of Health Research (CIHR) (to M. T.). 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 Supported by a thesis fellowship from the Ministère de la Recherche et de l'Enseignement Supérieur and by the Fondation pour la Recherche Médicale.

² Supported by the Leukemia and Lymphoma Society of America. Present address: Service de Biochimie et Génétique Moléculaire, CEA/Saclay, 91191 Gif-sur-Yvette, France.

³ Present address: Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France.

⁴ Supported by a Canada Research Chair in Functional Genomics and Bioinformatics.

⁵ To whom correspondence should be addressed. Tel.: 33-1-69-82-42-66; Fax: 33-1-69-82-42-38; E-mail: dthomas{at}cytomics.fr.

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