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J. Biol. Chem., Vol. 282, Issue 14, 10190-10202, April 6, 2007

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Sumoylation of the Transcriptional Intermediary Factor 1 (TIF1), the Co-repressor of the KRAB Multifinger Proteins, Is Required for Its Transcriptional Activity and Is Modulated by the KRAB Domain^*

From the Department of Biochemistry, Université de Montréal, Montréal, Québec H3C 3J7, Canada

Small ubiquitin-related modifier (SUMO) has emerged as a key post-translational modulator of protein functions. Here we show that TIF1, a developmental regulator proposed to act as a universal co-repressor for the large family of KRAB domain-containing zinc finger proteins, is a heavily SUMO-modified substrate. A combined analysis of deletion and punctual mutants identified TIF1 as a multilysine acceptor for SUMO which specifically targets six lysine residues (Lys⁵⁵⁴, Lys⁵⁷⁵, Lys⁶⁷⁶, Lys⁷⁵⁰, Lys⁷⁷⁹, and Lys⁸⁰⁴) within the TIF1 C-terminal repressive region. Reporter gene assays indicate that TIF1 requires SUMO-modification for its repressive activity. Indeed, sumoylation-less mutants failed to recapitulate TIF1-dependent repression. TIF1 homodimerization properties and interaction with the KRAB domain are preserved in the mutants with lysine to arginine substitutions as confirmed by in vivo bioluminescence resonance energy transfer (BRET). Using histone deacetylase (HDAC) inhibitors, we also demonstrate that TIF1 sumoylation is a prerequisite for the recruitment of HDAC and that TIF1 SUMO-dependent repressive activity involves both HDAC-dependent and HDAC-independent components. Finally, we report that, in addition to relying on the integrity of its PHD finger and on its self-oligomerization, TIF1 sumoylation is positively regulated by its interaction with KRAB domain-containing proteins. Altogether, our results provide new mechanistic insights into TIF1 transcriptional repression and suggest that KRAB multifinger proteins not only recruit TIF1 co-repressor to target genes but also increase its repressive activity through enhancement of its sumoylation.

Received for publication, December 13, 2006 , and in revised form, January 16, 2007.

^* This work was supported in part by a grant from Natural Sciences and Engineering Research Council of Canada (to M. A.) and a studentship from Fonds de la recherche en Santé du Québec (FRSQ) (to D. G.-D.). 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 A Chercheur National from FRSQ. To whom correspondence should be addressed: Département de biochimie, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montréal, Québec H3C 3J7, Canada. Tel.: 514-343-6322; Fax: 514-343-2210; E-mail: muriel.aubry{at}umontreal.ca.

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