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
  • 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, [email protected].
  • 7. From the Departments of Molecular Oncology and [email protected].
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).