TY - JOUR
T1 - HDAC3 deacetylates the DNA mismatch repair factor MutSβ to stimulate triplet repeat expansions
AU - Williams, Gregory M.
AU - Paschalis, Vasileios
AU - Ortega, Janice
AU - Muskett, Frederick W.
AU - Hodgkinson, James T.
AU - Li, Guo Min
AU - Schwabe, John W.R.
AU - Lahue, Robert S.
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported by Biotechnology and Biological Sciences Research Council (BBSRC)-Science Foundation Ireland Joint Funding of Research Award 16/BBSRC/3395 (to J.W.R.S. and R.S.L.), by the Irish Research Council Government of Ireland Postdoctoral Fellowship (to G.M.W.), and by the Cancer Prevention and Research Institute of Texas (CPRIT) Award RR160101 (to G.-M.L.). G.-M.L. is a CPRIT Scholar in Cancer Research.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/9/22
Y1 - 2020/9/22
N2 - 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.
AB - 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.
KW - Histone deacetylase 3
KW - Mismatch repair
KW - Triplet repeat expansion
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U2 - 10.1073/pnas.2013223117
DO - 10.1073/pnas.2013223117
M3 - Article
C2 - 32900932
AN - SCOPUS:85091589589
SN - 0027-8424
VL - 117
SP - 23597
EP - 23605
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 38
ER -