c-Jun-deficient cells undergo premature senescence as a result of spontaneous DNA damage accumulation

MacLaren, A., Black, E., Clark, W. and Gillespie, D. (2004) c-Jun-deficient cells undergo premature senescence as a result of spontaneous DNA damage accumulation. Molecular and Cellular Biology, 24(20), pp. 9006-9018. (doi: 10.1128/MCB.24.20.9006-9018.2004)

Abstract

Mouse embryo fibroblasts deficient for the c-Jun proto-oncogene (c-Jun(-/-) MEF) undergo p53-dependent premature senescence in conventional culture. This phenotype becomes evident only after several cell divisions, suggesting that senescence may result from exposure to unknown environmental factors. Here, we show that c-Jun(-/-) MEF can proliferate successfully in low oxygen (3% O-2), indicating that premature senescence under conventional culture conditions is a consequence of hyperoxic stress. c-Jun(-/-) MEF exhibit higher basal levels of DNA damage compared to normal fibroblasts in high but not low oxygen, implying that senescence results from chronic accumulation of spontaneous DNA damage. This accumulation may be attributable, at least in part, to inefficient repair, since DNA damage induced by gamma ionizing radiation and H2O2 persists for longer in c-Jun(-/-) MEF than in wild-type MEF. Unexpectedly, p53 expression, phosphorylation, and transcriptional activity are largely unaffected by oxygen exposure, indicating that the accumulation of spontaneous DNA damage does not result in chronic activation of p53 as judged by conventional criteria. Finally, we find that c-Jun associates with nuclear foci containing gammaH2AX and ATM following irradiation, suggesting a potential role for c-Jun in DNA repair processes per se.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gillespie, Professor David
• Authors: MacLaren, A., Black, E., Clark, W., and Gillespie, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular and Cellular Biology
• ISSN: 0270-7306