Abstract
Selenium induces a senescence response through induction of ataxia‐telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role for 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.
Published Version
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