MutS? 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 MutS? (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 MutS? subunits MSH2 or MSH3 impeded expansions of threshold-length repeats, while knockdown of the MutS? subunit MSH6 had no effect. Chromatin immunoprecipitation experiments indicated that MutS?, but not MutS?, was enriched at the TNR. These findings imply a direct role for MutS? 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 MutS?, HDAC3 and HDAC5 act through a common pathway to promote expansions of threshold-length TNRs.

SUBMITTER: Gannon AM 

PROVIDER: S-EPMC3488247 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature