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HDAC3 deacetylates the DNA mismatch repair factor MutS beta to stimulate triplet repeat expansions

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journal contribution
posted on 25.11.2020, 17:02 by Gregory M Williams, Vasileios Paschalis, Janice Ortega, Frederick W Muskett, James T Hodgkinson, Guo-Min Li, John WR Schwabe, Robert S Lahue
Trinucleotide repeat (TNR) expansions cause nearly 20 severe human neurological diseases which are currently untreatable. For some of these diseases, ongoing somatic expansions accelerate disease progression and may influence age of onset. This new knowledge emphasizes the importance of understanding the protein factors that drive expansions. Recent genetic evidence indicates that the mismatch repair factor MutSβ (Msh2-Msh3 complex) and the histone deacetylase HDAC3 function in the same pathway to drive triplet repeat expansions. Here we tested the hypothesis that HDAC3 deacetylates MutSβ and thereby activates it to drive expansions. The HDAC3-selective inhibitor RGFP966 was used to examine its biological and biochemical consequences in human tissue culture cells. HDAC3 inhibition efficiently suppresses repeat expansion without impeding canonical mismatch repair activity. Five key lysine residues in Msh3 are direct targets of HDAC3 deacetylation. In cells expressing Msh3 in which these lysine residues are mutated to arginine, the inhibitory effect of RGFP966 on expansions is largely bypassed, consistent with the direct deacetylation hypothesis. RGFP966 treatment does not alter MutSβ subunit abundance or complex formation but does partially control its subcellular localization. Deacetylation sites in Msh3 overlap a nuclear localization signal, and we show that localization of MutSβ is partially dependent on HDAC3 activity. Together, these results indicate that MutSβ is a key target of HDAC3 deacetylation and provide insights into an innovative regulatory mechanism for triplet repeat expansions. The results suggest expansion activity may be druggable and support HDAC3-selective inhibition as an attractive therapy in some triplet repeat expansion diseases.

History

Citation

vol. 117 no. 38 23597-23605

Author affiliation

Department of Molecular and Cell Biology

Version

VoR (Version of Record)

Published in

PNAS

Volume

117

Issue

38

Pagination

23597 - 23605 (9)

Publisher

National Academy of Sciences

issn

0027-8424

eissn

1091-6490

Copyright date

2020

Available date

08/09/2020

Spatial coverage

United States

Language

English