CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease.
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.
Jung
Joonil
J
Department of Biology, University of Pennsylvania, Philadelphila, PA 19104, USA.
Bonini
Nancy
N
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
D029721:Drosophila Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010455:Peptides; C097188:polyglutamine; C012589:trichostatin A; D050882:CREB-Binding Protein