HDAC6 regulates DNA damage response via deacetylating MLH1

Zhang, Mu; Hu, Chen; Moses, Niko; Haakenson, Joshua; Xiang, Shengyan; Quan, Daniel; Fang, Bin; Yang, Zhe; Bai, Wenlong; Bepler, Gerold; Li, Guo Min; Zhang, Xiaohong Mary

doi:10.1074/jbc.ra118.006374

Cited by 31 publications

(26 citation statements)

References 23 publications

(33 reference statements)

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“…Further molecular experiments indicated that HDAC3 knockdown did not alter the binding of MutS␤ at the repeat tract, or the expression level of MSH2 or MSH3, together suggesting an alternative hypothesis that HDAC3 modulates instability by regulating MSH2 or MSH3 acetylation. Indeed, activities of both MSH2 and MLH1 can be altered by acetylation [229][230][231], indicating that this is a plausible mechanism for instability modification by HDACs and HATs. Recent studies show that MSH3 peptides can be deacetylated by HDAC3 and that the nuclear localization of MSH3 is regulated by a selective HDAC3 inhibitor [232].…”

Section: Cis Elements Chromatin and Post Translational Modificationmentioning

confidence: 99%

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Wheeler

Dion

2021

JHD

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At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes a neurodegenerative or neuromuscular disease, the most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline and somatic instability of the causative CAG/CTG repeat mutations. Repeat lengthening, or expansion, in the germline leads to an earlier age of onset or more severe symptoms in the next generation. In somatic cells, repeat expansion is thought to precipitate the rate of disease. The mechanisms underlying repeat instability are not well understood. Here we review the mammalian model systems that have been used to study CAG/CTG repeat instability, and the modifiers identified in these systems. Mouse models have demonstrated prominent roles for proteins in the mismatch repair pathway as critical drivers of CAG/CTG instability, which is also suggested by recent genome-wide association studies in humans. We draw attention to a network of connections between modifiers identified across several systems that might indicate pathway crosstalk in the context of repeat instability, and which could provide hypotheses for further validation or discovery. Overall, the data indicate that repeat dynamics might be modulated by altering the levels of DNA metabolic proteins, their regulation, their interaction with chromatin, or by direct perturbation of the repeat tract. Applying novel methodologies and technologies to this exciting area of research will be needed to gain deeper mechanistic insight that can be harnessed for therapies aimed at preventing repeat expansion or promoting repeat contraction.

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Section: Cis Elements Chromatin and Post Translational Modificationmentioning

confidence: 99%

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Wheeler

Dion

2021

JHD

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“…A different class IIb enzyme, HDAC10, also interacts with Msh2, and MutSα-dependent MMR activity correlates positively with HDAC10 expression levels ( 71 ). The MutL homolog Mlh1 undergoes deacetylation by HDAC6 ( 72 ), which leads to blockage of assembly of MutSα-MutLα. In summary, there is precedent for class IIb HDAC-dependent regulation of MutSα and MutLα in canonical mismatch repair and response to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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

Williams

Paschalis

Ortega

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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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.

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“…Our data argue, at least for the Hdac2 KO, against altered transcription of genes encoding DNA repair proteins underlying the reduction in somatic expansion. However, it is possible that changes in acetylation of DNA repair proteins could lead to their altered activity ( Chatterjee et al, 2012 ; Choudhary et al, 2009 ; Zhang et al, 2014 ; Radhakrishnan et al, 2015 ; Piekna-Przybylska et al, 2016 ; Zhang et al, 2019 ). This was proposed as a plausible mechanism by which HDAC3 and HDAC5 enhance CAG expansion in a selectable human astrocyte cell-based assay, in part based on epistasis experiments showing that HDAC3 and HDAC5 act in the same pathway as MSH2 ( Debacker et al, 2012 ; Gannon et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice

Kovalenko

Erdin

Andrew

et al. 2020

eLife

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Somatic expansion of the Huntington's disease (HD) CAG repeat drives the rate of a pathogenic process ultimately resulting in neuronal cell death. Although mechanisms of toxicity are poorly delineated, transcriptional dysregulation is a likely contributor. To identify modifiers that act at the level of CAG expansion and/or downstream pathogenic processes, we tested the impact of genetic knockout, in HttQ111 mice, of Hdac2 or Hdac3 in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with Hdac2 knockout decreasing nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the HttQ111 allele, likely via mechanisms unrelated to instability suppression. Our results identify novel modifiers of different aspects of HD pathogenesis in MSNs and highlight a complex relationship between the expanded Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD.

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HDAC6 regulates DNA damage response via deacetylating MLH1

Cited by 31 publications

References 23 publications

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

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

Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice

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