title: Selenoprotein H suppresses cellular senescence through genome maintenance and redox regulation.
abstract: Oxidative stress and persistent DNA damage response contribute to cellular senescence, a degeneration process critically involving ataxia telangiectasia-mutated (ATM) and p53. Selenoprotein H (SelH), a nuclear selenoprotein, is proposed to carry redox and transactivation domains. To determine the role of SelH in genome maintenance, shRNA knockdown was employed in human normal and immortalized cell lines. SelH shRNA MRC-5 diploid fibroblasts under ambient O2 displayed a distinct profile of senescence including β-galactosidase expression, autofluorescence, growth inhibition, and ATM pathway activation. Such senescence phenotypes were alleviated in the presence of ATM kinase inhibitors, by p53 shRNA knockdown, or by maintaining the cells under 3% O2. During the course of 5-day recovery, the induction of phospho-ATM on Ser-1981 and γH2AX by H2O2 treatment (20 μm) subsided in scrambled shRNA but exacerbated in SelH shRNA MRC-5 cells. Results from clonogenic assays demonstrated hypersensitivity of SelH shRNA HeLa cells to paraquat and H2O2, but not to hydroxyurea, neocarzinostatin, or camptothecin. While SelH mRNA expression was induced by H2O2 treatment, SelH-GFP did not mobilize to sites of oxidative DNA damage. The glutathione level was lower in SelH shRNA than scrambled shRNA HeLa cells, and the H2O2-induced cell death was rescued in the presence of N-acetylcysteine, a glutathione precursor. Altogether, SelH protects against cellular senescence to oxidative stress through a genome maintenance pathway involving ATM and p53.
authors.affiliation: From the Department of Nutrition and Food Science, University of Maryland, College Park, Maryland 20742.
authors.forename: Ryan T Y
authors.initials: RT
authors.lastname: Wu
authors.affiliation: Department of Food Science, Nutrition, and Health Promotion, Mississippi State University, Mississippi State, Mississippi 39762, and.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Division of Molecular Radiation Biology, Department of Radiation Oncology, Southwestern Medical Center at Dallas, University of Texas, Dallas, Texas 75390.
authors.forename: Benjamin P C
authors.initials: BP
authors.lastname: Chen
authors.affiliation: From the Department of Nutrition and Food Science, University of Maryland, College Park, Maryland 20742, Department of Food Science, Nutrition, and Health Promotion, Mississippi State University, Mississippi State, Mississippi 39762, and wc523@msstate.edu.
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Cheng
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D015894:Genome, Human; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051140:Selenoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D051140:Selenoproteins; D016159:Tumor Suppressor Protein p53; C519118:selenoprotein H, human; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D001616:beta-Galactosidase; D010269:Paraquat; D000111:Acetylcysteine
keywords: Ataxia Telangiectasia; Reactive Oxygen Species (ROS); Selenium; Senescence; p53