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Originally published In Press as doi:10.1074/jbc.M205259200 on September 23, 2002

J. Biol. Chem., Vol. 277, Issue 47, 45004-45012, November 22, 2002
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Ataxin-3 Is a Histone-binding Protein with Two Independent Transcriptional Corepressor Activities*

Fusheng Li, Todd Macfarlan, Randall N. PittmanDagger , and Debabrata Chakravarti§

From the Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084

The mechanisms of pathology for the family of polyglutamine disease proteins are unknown; however, recently it was shown that several of these proteins inhibit transcription suggesting that transcriptional repression may be a potential mechanism for pathology. In the present study we use cell transfections, in vitro binding, co-immunoprecipitations, and reporter assays to show that the polyglutamine disease protein, ataxin-3, interacts with the major histone acetyltransferases cAMP-response-element binding protein (CREB)-binding protein, p300, and p300/CREB-binding protein-associated factor and inhibits transcription by these coactivators. Importantly, endogenous ataxin-3 is co-immunoprecipitated with each of these coactivators in non-transfected cells. The C-terminal polyglutamine-containing domain of ataxin-3 inhibits coactivator-dependent transcription and is required for binding coactivators. The N-terminal domain of ataxin-3 inhibits histone acetylation by p300 in vitro and inhibits transcription in vivo. Histone binding and blocking access of coactivators to acetylation sites on histones appears to be the mechanism of inhibition. Together, our data provide a novel mechanism of transcriptional regulation by ataxin-3 that involves targeting histones, coactivators, and an independent mode of direct repression of transcription, and suggests that its physiological function and possibly pathological effects are linked to its interactions with these proteins.

* This work was supported by National Institutes of Health Grants NS42625 (to R. N. P.) and DK57079 (D. C.).

Dagger To whom correspondence may be addressed. Tel.: 215-898-9736; Fax: 215-573-2236; E-mail: pittman@pharm.med.upenn.edu.

§ To whom correspondence may be addressed. Tel.: 215-573-8470; Fax: 215-573-9004; E-mail: debu@pharm.med.upenn.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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