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

Abstract

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