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J. Biol. Chem., Vol. 281, Issue 32, 23180-23190, August 11, 2006

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Involvement of SUMO Modification in MBD1- and MCAF1-mediated Heterochromatin Formation^*

Yasuhiro Uchimura¹, Takaya Ichimura, Junsuke Uwada, Taro Tachibana, Satoko Sugahara, Mitsuyoshi Nakao, and Hisato Saitoh²

From the Department of Regeneration Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811 and Department of Bioengineering, Graduate School of Engineering, Osaka City University, Osaka 558-8585, Japan

Small ubiquitin-related modifiers, SUMO-2/3 and SUMO-1, are involved in gene regulation and nuclear structures. However, little is known about the roles of SUMO, in heterochromatin formation of mammalian cells. Here we demonstrate that SUMOs directly interact with human MCAF1, which forms complexes with either the methyl-CpG-binding protein MBD1 or SETDB1, which trimethylates histone H3 at lysine 9 (H3-K9) in the presence of MCAF1. Modification of MBD1 with either SUMO-2/3 or SUMO-1 facilitated the interaction between MBD1 and MCAF1, suggesting that SUMOylation links the methylation of DNA and histones. In a cultured human cell line, SUMOs were localized in MBD1- and MCAF1-containing heterochromatin regions that were enriched in trimethyl-H3-K9 and the heterochromatin proteins HP1 and HP1. Specific knockdown of either SUMO-2/3 or SUMO-1 induced dissociation of MCAF1, trimethyl-H3-K9, and the HP1 proteins from the MBD1-containing heterochromatin foci, suggesting a requirement for SUMOs for heterochromatin assembly. These findings provide insights into the roles of SUMOylation in the regulation of heterochromatin formation and gene silencing.

Received for publication, March 10, 2006 , and in revised form, May 30, 2006.

This work is dedicated to the late S. Mizuno, who was an excellent mentor to H. S. during his graduate studies at Tohoku University, Sendai, Japan, and the late A. P. Wolffe, who was a good advisor to H. S. during his postdoctoral training at the National Institutes of Health, Bethesda. Their enthusiasm and curiosity were the motivation behind this study to find a link between the SUMO modification pathway and the mechanisms behind chromatin dynamics and epigenetic control.

^* This work was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology and by a COE grant from MEXT Japan. 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 A research fellow of the Japan Society for the Promotion of Science.

² To whom correspondence should be addressed: Dept. of Biological Science, Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8555, Japan. Tel.: 81-96-342-3450; Fax: 81-96-342-3450; E-mail: hisa{at}gpo.kumamoto-u.ac.jp.

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