2. Academic Validation
  3. Histone deacetylase 10 regulates DNA mismatch repair and may involve the deacetylation of MutS homolog 2

Histone deacetylase 10 regulates DNA mismatch repair and may involve the deacetylation of MutS homolog 2

  • J Biol Chem. 2015 Sep 11;290(37):22795-804. doi: 10.1074/jbc.M114.612945.
Rangasudhagar Radhakrishnan 1,  Yixuan Li 1,  Shengyan Xiang 2,  Fenghua Yuan 3,  Zhigang Yuan 1,  Elphine Telles 1,  Jia Fang 1,  Domenico Coppola 4,  David Shibata 4,  William S Lane 5,  Yanbin Zhang 3,  Xiaohong Zhang 6,  Edward Seto 7
Affiliations

Affiliations

  • 1 From the Departments of Molecular Oncology and.
  • 2 the Department of Pathology and Cell Biology, University of South Florida (USF) Morsani College of Medicine, Tampa, Florida 33612.
  • 3 the Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, and.
  • 4 Gastroenterology, and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
  • 5 the Mass Spectrometry and Proteomics Resource Laboratory, Harvard University, Cambridge, Massachusetts 02138.
  • 6 From the Departments of Molecular Oncology and the Department of Pathology and Cell Biology, University of South Florida (USF) Morsani College of Medicine, Tampa, Florida 33612, xzhang1@health.usf.edu.
  • 7 From the Departments of Molecular Oncology and ed.seto@moffitt.org.
PMID: 26221039 DOI: 10.1074/jbc.M114.612945
Abstract

MutS homolog 2 (MSH2) is an essential DNA mismatch repair (MMR) protein. It interacts with MSH6 or MSH3 to form the MutSα or MutSβ complex, respectively, which recognize base-base mispairs and insertions/deletions and initiate the repair process. Mutation or dysregulation of MSH2 causes genomic instability that can lead to Cancer. MSH2 is acetylated at its C terminus, and histone deacetylase (HDAC6) deacetylates MSH2. However, whether other regions of MSH2 can be acetylated and whether other histone deacetylases (HDACs) and histone acetyltransferases (HATs) are involved in MSH2 deacetylation/acetylation is unknown. Here, we report that MSH2 can be acetylated at Lys-73 near the N terminus. Lys-73 is highly conserved across many species. Although several Class I and II HDACs interact with MSH2, HDAC10 is the major Enzyme that deacetylates MSH2 at Lys-73. Histone Acetyltransferase HBO1 might acetylate this residue. HDAC10 overexpression in HeLa cells stimulates cellular DNA MMR activity, whereas HDAC10 knockdown decreases DNA MMR activity. Thus, our study identifies an HDAC10-mediated regulatory mechanism controlling the DNA mismatch repair function of MSH2.

Keywords

DNA mismatch repair; histone acetylase; histone deacetylase (HDAC); histone deacetylase inhibitor (HDAC inhibitor) (HDI); post-translational modification (PTM).

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