期刊
MOLECULAR CANCER RESEARCH
卷 5, 期 10, 页码 1083-1098出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-06-0432
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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-downstrearn 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.
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