title: HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα.
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.
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
authors.forename: Mu
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
authors.forename: Shengyan
authors.initials: S
authors.lastname: Xiang
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Kaul Human Genetics Building 402A, 720 South 20th Street, Birmingham, AL 35294, USA.
authors.forename: Heui-Yun
authors.initials: HY
authors.lastname: Joo
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
authors.forename: Kendra A
authors.initials: KA
authors.lastname: Williams
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
authors.forename: Wei
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authors.lastname: Liu
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
authors.forename: Chen
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authors.lastname: Hu
authors.affiliation: Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Tong
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Haakenson
authors.affiliation: Key Laboratory of Medical Cell Biology, Institute for Translational Medicine, China Medical University, Shengyang 110000, China.
authors.forename: Chuangui
authors.initials: C
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authors.affiliation: Key Laboratory of Medical Cell Biology, Institute for Translational Medicine, China Medical University, Shengyang 110000, China.
authors.forename: Shengping
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authors.affiliation: Biophysics Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Pavlovicz
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Kaul Human Genetics Building 402A, 720 South 20th Street, Birmingham, AL 35294, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Jones
authors.affiliation: 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.
authors.forename: Kristina H
authors.initials: KH
authors.lastname: Schmidt
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
authors.forename: Jinfu
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
authors.forename: Huiqin
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authors.affiliation: Medical Sciences, Washington State University at Spokane, 412E Spokane Falls Boulevard, Spokane, WA 99201, USA.
authors.forename: Bin
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authors.affiliation: Proteomics, SRB-3, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Bin
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authors.affiliation: Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Rangasudhagar
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authors.lastname: Radhakrishnan
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, 4058 Basel, Switzerland.
authors.forename: Patrick
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authors.lastname: Matthias
authors.affiliation: Proteomics, SRB-3, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: John
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authors.affiliation: Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
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authors.lastname: Seto
authors.affiliation: Molecular Therapeutics Program, Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, USA.
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.affiliation: 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.
authors.forename: Santo V
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authors.affiliation: Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Jiandong
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authors.affiliation: 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.
authors.forename: Chenglong
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authors.affiliation: Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Liya
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authors.lastname: Gu
authors.affiliation: Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Bai
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Kaul Human Genetics Building 402A, 720 South 20th Street, Birmingham, AL 35294, USA.
authors.forename: Hengbin
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xiaohong
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authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D055550:Protein Stability; D054875:Ubiquitination
chemical_list: C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein