HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα

Mu Zhang; Shengyan Xiang; Heui-Yun Joo; Lei Wang; Kendra A Williams; Wei Liu; Chen Hu; Dan Tong; Joshua Haakenson; Chuangui Wang; Shengping Zhang; Ryan E Pavlovicz; Amanda Jones; Kristina H Schmidt; Jinfu Tang; Huiqin Dong; Bin Shan; Bin Fang; Rangasudhagar Radhakrishnan; Peter M Glazer; Patrick Matthias; John Koomen; Edward Seto; Gerold Bepler; Santo V Nicosia; Jiandong Chen; Chenglong Li; Liya Gu; Guo-Min Li; Wenlong Bai; Hengbin Wang; Xiaohong Zhang

doi:10.1016/j.molcel.2014.04.028

HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα

Mol Cell. 2014 Jul 3;55(1):31-46. doi: 10.1016/j.molcel.2014.04.028. Epub 2014 May 29.

Authors

Mu Zhang¹, Shengyan Xiang¹, Heui-Yun Joo², Lei Wang¹, Kendra A Williams¹, Wei Liu¹, Chen Hu¹, Dan Tong³, Joshua Haakenson¹, Chuangui Wang⁴, Shengping Zhang⁴, Ryan E Pavlovicz⁵, Amanda Jones², Kristina H Schmidt⁶, Jinfu Tang¹, Huiqin Dong¹, Bin Shan⁷, Bin Fang⁸, Rangasudhagar Radhakrishnan⁹, Peter M Glazer¹⁰, Patrick Matthias¹¹, John Koomen⁸, Edward Seto⁹, Gerold Bepler¹², Santo V Nicosia¹³, Jiandong Chen⁹, Chenglong Li¹⁴, Liya Gu³, Guo-Min Li³, Wenlong Bai¹⁵, Hengbin Wang², Xiaohong Zhang¹⁶

Affiliations

¹ Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
² Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Kaul Human Genetics Building 402A, 720 South 20th Street, Birmingham, AL 35294, USA.
³ Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
⁴ Key Laboratory of Medical Cell Biology, Institute for Translational Medicine, China Medical University, Shengyang 110000, China.
⁵ Biophysics Program, The Ohio State University, Columbus, OH 43210, USA.
⁶ Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33620, USA; Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁷ Medical Sciences, Washington State University at Spokane, 412E Spokane Falls Boulevard, Spokane, WA 99201, USA.
⁸ Proteomics, SRB-3, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁹ Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
¹⁰ Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
¹¹ Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, 4058 Basel, Switzerland.
¹² Molecular Therapeutics Program, Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, USA.
¹³ Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA; Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
¹⁴ Biophysics Program, The Ohio State University, Columbus, OH 43210, USA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
¹⁵ Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA; Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
¹⁶ Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA; Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Electronic address: xzhang1@health.usf.edu.

Abstract

MutS protein homolog 2 (MSH2) is a key DNA mismatch repair protein. It forms the MSH2-MSH6 (MutSα) and MSH2-MSH3 (MutSβ) heterodimers, which help to ensure genomic integrity. MutSα not only recognizes and repairs mismatched nucleotides but also recognizes DNA adducts induced by DNA-damaging agents, and triggers cell-cycle arrest and apoptosis. Loss or depletion of MutSα from cells leads to microsatellite instability (MSI) and resistance to DNA damage. Although the level of MutSα can be reduced by the ubiquitin-proteasome pathway, the detailed mechanisms of this regulation remain elusive. Here we report that histone deacetylase 6 (HDAC6) sequentially deacetylates and ubiquitinates MSH2, leading to MSH2 degradation. In addition, HDAC6 significantly reduces cellular sensitivity to DNA-damaging agents and decreases cellular DNA mismatch repair activities by downregulation of MSH2. Overall, these findings reveal a mechanism by which proper levels of MutSα are maintained.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Cells, Cultured
HEK293 Cells
HeLa Cells
Histone Deacetylase 6
Histone Deacetylases / genetics
Histone Deacetylases / metabolism
Histone Deacetylases / physiology*
Humans
Mice
MutS Homolog 2 Protein / metabolism*
Protein Stability
Ubiquitination

Substances

HDAC6 protein, human
Histone Deacetylase 6
Histone Deacetylases
MSH2 protein, human
MutS Homolog 2 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding