Abstract
Abstract Selenium induces a senescence response through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the DNA-PK complex, including the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), Ku70 and Ku80, in DNA double strand break repair is established, it is unclear how these proteins function in the response to selenium-induced oxidative stress and senescence induction. In this study we demonstrate that pre-treating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppresses selenium-induced senescence response. Selenium treatment induces phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which is decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidant N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 is not affected by NU 7026. Cells deficient in DNA-PKcs or pre-treated with NU 7026 or N-acetylcysteine are defective in selenite-induced ROS formation. Opposed to DNA-PKcs, Ku70 and Ku80 are dispensable for selenite-induced ROS and γH2A.X formation and removal. Taken together, these results indicate a distinct role of DNA-PKcs from Ku70 and Ku80, 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5425. doi:1538-7445.AM2012-5425
Published Version
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