title: CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease.
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.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphila, PA 19104, USA.
authors.forename: Joonil
authors.initials: J
authors.lastname: Jung
authors.forename: Nancy
authors.initials: N
authors.lastname: Bonini
mesh_terms: D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D020132:Anticipation, Genetic; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics*; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics; D042822:Genomic Instability; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D006877:Hydroxamic Acids / Q000494:pharmacology; D017827:Machado-Joseph Disease / Q000235:genetics*; D008297:Male; D023421:Models, Animal; D010455:Peptides / Q000737:chemistry; D014158:Transcription, Genetic; D019076:Transgenes; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats
chemical_list: D029721:Drosophila Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010455:Peptides; C097188:polyglutamine; C012589:trichostatin A; D050882:CREB-Binding Protein