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Originally published in Science Express on 1 March 2007
Science 30 March 2007:
Vol. 315. no. 5820, pp. 1857 - 1859
DOI: 10.1126/science.1139517
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Reports

CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease

Joonil Jung1 and Nancy Bonini1,2*

Although expansion of trinucleotide repeats accounts for over 30 human diseases, mechanisms of repeat instability remain poorly understood. We show that a Drosophila model for the CAG/polyglutamine (polyQ) disease spinocerebellar ataxia type 3 recapitulates key features of human CAG-repeat instability, including large repeat changes and strong expansion bias. Instability is dramatically enhanced by transcription and modulated by nuclear excision repair and a regulator of DNA repair adenosine 3',5'-monophosphate (cAMP) response element–binding protein (CREB)–binding protein—a histone acetyltransferase (HAT) whose decreased activity contributes to polyQ disease. Pharmacological treatment to normalize acetylation suppressed instability. Thus, toxic consequences of pathogenic polyQ protein may include enhancing repeat instability.

1 Department of Biology, University of Pennsylvania, Philadelphila, PA 19104, USA.
2 Howard Hughes Medical Institute, University of Pennsylvania, Philadelphila, PA 19104, USA.

* To whom correspondence should be addressed. E-mail: nbonini{at}sas.upenn.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)