CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease.

Full Abstract

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.

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Author information

Author/s: Jung, Joonil (J); Bonini, Nancy (N);

Affiliation: Department of Biology, University of Pennsylvania, Philadelphila, PA 19104, USA.

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Science (New York, N.Y.) (Science), published in United States. (Language: eng)

Reference: 2007-Mar; vol 315 (issue 5820) : pp 1857-9

Dates: Created 2007/03/30; Completed 2007/04/12;

PMID: 17332375, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentIn: Science. 2007 Mar 30;315(5820):1800-1. (PMID: 17395816)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Alleles
Animals
Animals, Genetically Modified
Anticipation, Genetic
CREB-Binding Protein - genetics; metabolism
DNA Repair
Drosophila Proteins - genetics; metabolism
Drosophila melanogaster - genetics
Female
Fragile X Syndrome - genetics
Genomic Instability
Histone Deacetylases - antagonists & inhibitors

Histone Deacetylases - antagonists & inhibitors
Humans
Huntington Disease - genetics
Hydroxamic Acids - pharmacology
Machado-Joseph Disease - genetics
Male
Models, Animal
Peptides - chemistry
Transcription, Genetic
Transgenes
Trinucleotide Repeat Expansion
Trinucleotide Repeats

Associated Chemicals: Drosophila Proteins (0) ; Hydroxamic Acids (0) ; Peptides (0) ; polyglutamine (26700-71-0) ; trichostatin A (58880-19-6) ; CREB-Binding Protein (EC 2.3.1.48) ; Histone Deacetylases (EC 3.5.1.-)

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