Telomeric DNA induces p53-dependent reactive oxygen species and protects against oxidative damage

• Published in: Journal of dermatological science 2009-12, Vol.56 (3), p.154-162
• Main Authors: Lee, Margaret S, Yaar, Mina, Eller, Mark S, Rünger, Thomas M, Gao, Ying, Gilchrest, Barbara A
• Format: Article
• Language: English
• Subjects: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins - metabolism; Cell Line; Checkpoint Kinase 2; Dermatology; DNA - metabolism; DNA Damage - drug effects; DNA Damage - physiology; DNA damage responses; DNA Repair - drug effects; DNA Repair - physiology; DNA-Binding Proteins - metabolism; Fibroblasts - drug effects; Fibroblasts - metabolism; Histones - metabolism; Humans; NADPH Oxidases - metabolism; Oligonucleotides - chemistry; Oligonucleotides - genetics; Oligonucleotides - pharmacology; Oxidative stress; Oxidative Stress - drug effects; Protein-Serine-Threonine Kinases - metabolism; Reactive Oxygen Species - agonists; Reactive Oxygen Species - metabolism; Senescence; Signal Transduction - drug effects; Signal Transduction - physiology; T-oligos; Telomere; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/j.jdermsci.2009.08.008

Abstract Background Reactive oxygen species (ROS) are generated by cellular metabolism as well as by exogenous agents. While ROS can promote cellular senescence, they can also act as signaling molecules for processes that do not lead to senescence. Telomere homolog oligonucleotides (T-oligos) induce adaptive DNA damage responses including increased DNA repair capacity and these effects are mediated, at least in part, through p53. Objective Studies were undertaken to determine whether such p53-mediated protective responses include enhanced antioxidant defenses. Methods Normal human fibroblasts as well as R2F fibroblasts expressing wild type or dominant negative p53 were treated with an 11-base T-oligo, a complementary control oligo or diluents alone and then examined by western blot analysis, immunofluorescence microscopy and various biochemical assays. Results We now report that T-oligo increases the level of the antioxidant enzymes superoxide dismutase 1 and 2 and protects cells from oxidative damage; and that telomere-based γH2AX (DNA damage) foci that form in response to T-oligos contain phosphorylated ATM and Chk2, proteins known to activate p53 and to mediate cell cycle arrest in response to oxidative stress. Further, T-oligo increases cellular ROS levels via a p53-dependent pathway, and these increases are abrogated by the NAD(P)H oxidase inhibitor diphenyliodonium chloride. Conclusion These results suggest the existence of innate telomere-based protective responses that act to reduce oxidative damage to cells. T-oligo treatment induces the same responses and offers a new model for studying intracellular ROS signaling and the relationships between DNA damage, ROS, oxidative stress, and cellular defense mechanisms.