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bioRxiv · 10.1101/2024.09.29.615664

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

Guo, J.·Yang, W.·Li, G.-M.
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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.

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Guo, J., Yang, W., Li, G.-M.. 2024-09-29. Interaction between histone residue H3K56 and mismatch repair protein MutSβ drives CAG repeat expansion. https://doi.org/10.1101/2024.09.29.615664

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