Mutsβ and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells
Gannon, Anne-Marie M.
Lahue, Robert S.
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Gannon, Anne-Marie M. Frizzell, Aisling; Healy, Evan; Lahue, Robert S. (2012). Mutsβ and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells. Nucleic Acids Research 40 (20), 10324-10333
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 beta (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 (similar to 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 center dot CAG repeats in a human astrocytic cell line. siRNA knockdown of the MutS beta subunits MSH2 or MSH3 impeded expansions of threshold-length repeats, while knockdown of the MutS alpha subunit MSH6 had no effect. Chromatin immunoprecipitation experiments indicated that MutS beta, but not MutS alpha, was enriched at the TNR. These findings imply a direct role for MutS beta in promoting expansion of threshold-length CTG center dot 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 beta, HDAC3 and HDAC5 act through a common pathway to promote expansions of threshold-length TNRs.