title: The catalytic subunit of DNA-dependent protein kinase is downstream of ATM and feeds forward oxidative stress in the selenium-induced senescence response.
abstract: Selenium induces a senescence response in cells through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in DNA double-strand break repair is established, it is unclear how these proteins function in response to selenium-induced oxidative stress and senescence induction. In this study, we demonstrated that pretreating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppressed selenium-induced senescence response. Selenium treatment induced phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which was decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidants N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 was not affected by NU 7026. Cells deficient in DNA-PKcs or pretreated with NU 7026 or N-acetylcysteine were defective in selenite-induced ROS formation. Taken together, these results indicate a distinct role of DNA-PKcs, in which this kinase can respond to and feed forward selenium-induced ROS formation and is placed downstream of ATM in the resultant senescence response.
authors: Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA.
authors: Caroline R B
authors: CR
authors: Rocourt
authors: Min
authors: M
authors: Wu
authors: Benjamin P C
authors: BP
authors: Chen
authors: Wen-Hsing
authors: WH
authors: Cheng
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003911:Dextrans / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D011753:Pyrones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020887:Selenious Acid / Q000494:pharmacology; D012643:Selenium / Q000494:pharmacology*
chemical_list: C437404:2,2,6,6-tetramethylpiperidine-1-oxyldextran; C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D000975:Antioxidants; D002867:Chromones; D003911:Dextrans; D009025:Morpholines; D011753:Pyrones; D017382:Reactive Oxygen Species; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; D020887:Selenious Acid; D012643:Selenium; D000111:Acetylcysteine