title: MutSβ and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells.
abstract: Trinucleotide repeat (TNR) expansions cause at least 17 heritable neurological diseases, including Huntington's disease. Expansions are thought to arise from abnormal processing of TNR DNA by specific trans-acting proteins. For example, the DNA repair complex MutSβ (MSH2-MSH3 heterodimer) is required in mice for on-going expansions of long, disease-causing alleles. A distinctive feature of TNR expansions is a threshold effect, a narrow range of repeat units (∼30-40 in humans) at which mutation frequency rises dramatically and disease can initiate. The goal of this study was to identify factors that promote expansion of threshold-length CTG•CAG repeats in a human astrocytic cell line. siRNA knockdown of the MutSβ subunits MSH2 or MSH3 impeded expansions of threshold-length repeats, while knockdown of the MutSα subunit MSH6 had no effect. Chromatin immunoprecipitation experiments indicated that MutSβ, but not MutSα, was enriched at the TNR. These findings imply a direct role for MutSβ in promoting expansion of threshold-length CTG•CAG tracts. We identified the class II deacetylase HDAC5 as a novel promoting factor for expansions, joining the class I deacetylase HDAC3 that was previously identified. Double knockdowns were consistent with the possibility that MutSβ, HDAC3 and HDAC5 act through a common pathway to promote expansions of threshold-length TNRs.
authors.affiliation: Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: Anne-Marie M
authors.initials: AM
authors.lastname: Gannon
authors.forename: Aisling
authors.initials: A
authors.lastname: Frizzell
authors.forename: Evan
authors.initials: E
authors.lastname: Healy
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lahue
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000074081:MutS Homolog 3 Protein; D019680:Trinucleotide Repeat Expansion; D000099186:Histone Deacetylase 3
chemical_list: D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D000099186:Histone Deacetylase 3; C078444:MSH3 protein, human; C404500:HDAC5 protein, human; C497172:MSH2 protein, human