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DNA Damage and Cellular Stress Responses

Human 8-Oxoguanine DNA Glycosylase Suppresses the Oxidative Stress–Induced Apoptosis through a p53-Mediated Signaling Pathway in Human Fibroblasts

¹ Korean DNA Repair Research Center, Departments of ² Pharmacology, ³ Obstetrics and Gynecology, and ⁴ Anatomy, Chosun University School of Medicine, Gwangju, South Korea; ⁵ Department of Dermatology, University of Colorado Health Sciences Center, Denver, Colorado; ⁶ Department of Herbal Pharmaceutical Development, Korea Institute of Oriental Medicine, Daejeon, South Korea; ⁷ Department of Biochemistry, College of Medicine, Cheju National University, Jeju-do, South Korea; ⁸ Department of Anatomy, College of Medicine, Seonam University, Jeollabuk-Do, South Korea; and ⁹ Department of Pharmacology, School of Medicine, Seoul National University, Seoul, South Korea

Requests for reprints: Ho Jin You, Korean DNA Repair Research Center, Bio Engineering BD 2F, Department of Pharmacology, Chosun University School of Medicine, 375 Seosuk-Dong, Gwangju 501-759, Republic of Korea. Phone: 82-62-230-6337; Fax: 82-62-230-6586. E-mail: hjyou{at}chosun.ac.kr

Human 8-oxoguanine DNA glycosylase (hOGG1) is the main defense enzyme against mutagenic effects of cellular 7,8-dihydro-8-oxoguanine. In this study, we investigated the biological role of hOGG1 in DNA damage–related apoptosis induced by hydrogen peroxide (H₂O₂)–derived oxidative stress. The down-regulated expression of hOGG1 by its small interfering RNA prominently triggers the H₂O₂-induced apoptosis in human fibroblasts GM00637 and human lung carcinoma H1299 cells via the p53-mediated apoptotic pathway. However, the apoptotic responses were specifically inhibited by hOGG1 overexpression. The p53–small interfering RNA transfection into the hOGG1-deficient GM00637 markedly inhibited the H₂O₂-induced activation of p53-downstream target proteins such as p21, Noxa, and caspase-3/7, which eventually resulted in the increased cell viability. Although the cell viability of hOGG1-knockdown H1299 p53 null cells was similar to that of the hOGG1 wild-type H1299, after the overexpression of p53 the hOGG1-knockdown H1299 showed the significantly decreased cell viability compared with that of the hOGG1 wild-type H1299 at the same experimental condition. Moreover, the array comparative genome hybridization analyses revealed that the hOGG1-deficient GM00637 showed more significant changes in the copy number of large regions of their chromosomes in response to H₂O₂ treatment. Therefore, we suggest that although p53 is a major modulator of apoptosis, hOGG1 also plays a pivotal role in protecting cells against the H₂O₂-induced apoptosis at the upstream of the p53-dependent pathway to confer a survival advantage to human fibroblasts and human lung carcinomas through maintaining their genomic stability. (Mol Cancer Res 2007;5(10):1083–98)