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J. Biol. Chem., Vol. 283, Issue 13, 8283-8290, March 28, 2008

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Polyglutamine Expansion Reduces the Association of TATA-binding Protein with DNA and Induces DNA Binding-independent Neurotoxicity^*

From the Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322

TATA-binding protein (TBP) is essential for eukaryotic gene transcription. Human TBP contains a polymorphic polyglutamine (polyQ) domain in its N terminus and a DNA-binding domain in its highly conserved C terminus. Expansion of the polyQ domain to >42 glutamines typically results in spinocerebellar ataxia type 17 (SCA17), a neurodegenerative disorder that resembles Huntington disease. Our recent studies have demonstrated that polyQ expansion causes abnormal interaction of TBP with the general transcription factor TFIIB and induces neurodegeneration in transgenic SCA17 mice (Friedman, M. J., Shah, A. G., Fang, Z. H., Ward, E. G., Warren, S. T., Li, S., and Li, X. J. (2007) Nat. Neurosci. 10, 1519–1528). However, it remains unknown how polyQ expansion influences DNA binding by TBP. Here we report that polyQ expansion reduces in vitro binding of TBP to DNA and that mutant TBP fragments lacking an intact C-terminal DNA-binding domain are present in transgenic SCA17 mouse brains. polyQ-expanded TBP with a deletion spanning part of the DNA-binding domain does not bind DNA in vitro but forms nuclear aggregates and inhibits TATA-dependent transcription activity in cultured cells. When this TBP double mutant is expressed in transgenic mice, it forms nuclear inclusions in neurons and causes early death. These findings suggest that the polyQ tract affects the binding of TBP to promoter DNA and that polyQ-expanded TBP can induce neuronal toxicity independent of its interaction with DNA.

Received for publication, November 27, 2007 , and in revised form, January 23, 2008.

^* This work was supported by National Institutes of Health Grants AG019206, NS045106, and NS041669. 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 and S2.

¹ To whom correspondence may be addressed: Dept. of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-3290; Fax: 404-727-2949; E-mail: xiaoli{at}genetics.emory.edu. ² To whom correspondence may be addressed: Dept. of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-3290; Fax: 404-727-2949; E-mail: shihual{at}genetics.emory.edu.

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