Interaction between histone residue H3K56 and mismatch repair protein MutSβ drives CAG repeat expansion

DNA repair protein MutSβ promotes CAG repeat expansions, which cause ~20 untreatable neurodegenerative disorders including Huntington's disease (HD). However, how MutSβ is recruited onto chromatin to enable repeat expansion is unknown. Here, we show that H3K56 interacts with MutSβ and brings it to chromatin. The H3K56-MutSβ interaction is regulated by H3K56 acetylation (H3K56ac) conditions, with acetylation inhibiting but deacetylation facilitating MutSβ chromatin recruitment. Blocking the H3K56-MutSβ interaction by either disrupting the MutSβ aromatic packet or increasing the H3K56ac level by removing histone deacetylases stabilizes CAG repeats, while depleting histone acetyltransferase p300/CBP promotes the H3K56-MutSβ interaction and CAG repeat instability, including expansion of CAG repeats of the huntingtin gene. Therefore, our study suggests a novel mechanism, by which MutSβ induces triplet repeat expansion, and new strategies of blocking the H3K56-MutSβ interaction to prevent HD and other triplet repeat expansion-caused disorders.