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J. Biol. Chem., Vol. 283, Issue 17, 11586-11595, April 25, 2008

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SUMOylation Modulates the Transcription Repressor Function of RIP140^*

From the Institute of Biomedicine/Medical Biochemistry, University of Kuopio, FI-70211 Kuopio, Finland

RIP140/NRIP1 (receptor-interacting protein 140) functions as a corepressor of nuclear receptors. It plays an important role in the transcriptional control of energy metabolism and female fertility. RIP140 contains four distinct repression domains (RD1–RD4), and the repressive activity of RIP140 involves complex mechanisms. The function of both RD1 and RD2 is linked to recruitment of histone deacetylases and C-terminal binding protein, respectively, but the mechanism of repression for RD3 and RD4 has remained elusive. Because covalent modification by small ubiquitin-like modifiers (SUMO-1, -2, and -3; SUMOylation) is often associated with transcriptional repression, we studied whether SUMOylation is involved in the repressive activity of RIP140. We show that two conserved lysines, Lys⁷⁵⁶ and Lys¹¹⁵⁴, located in RD3 and RD4, respectively, are subject to reversible SUMOylation, with SUMO-1 being more efficiently conjugated than SUMO-2. Interestingly, mutations of the RIP140 SUMOylation sites compromised the transcription repressor function of RIP140 and blunted its capacity to repress estrogen receptor -dependent transcription. Conjugation of SUMO-1 also influenced the subnuclear distribution pattern of RIP140. In sum, our demonstration that the function of RIP140 repression domains 3 and 4 can be modulated by reversible SUMO modification thus adds a novel level to the regulation of RIP140 activity, which may have ramifications in the control of gene networks exerted by RIP140.

Received for publication, November 14, 2007 , and in revised form, January 11, 2008.

^* This work was supported by grants from the Academy of Finland, the Association for International Cancer Research, the Finnish Cancer Foundation, and the Sigrid Jusélius Foundation. 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: Institute of Biomedicine/Medical Biochemistry, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland. Tel.: 358-17-163109; Fax: 353-17-2811510; E-mail: jorma.palvimo{at}uku.fi.

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