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Published Online March 1, 2007
Science DOI: 10.1126/science.1139517

Reports

Submitted on January 4, 2007
Accepted on February 9, 2007

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

Joonil Jung 1 and Nancy Bonini 2*

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

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

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 (SCA3) 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 CREB-binding protein (CBP)--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.


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