DNA damage mediated by reactive oxygen species is believed to contribute to the etiology of human cancer and aging, and possibly to brain and cardiac tissue damage associated with ischemic events. Critical examination of this hypothesis has been difficult since few experimental models are available in which oxidative DNA damage can be studied at the whole animal level. We recently cloned the human and mouse homologs of yeast ogg1, a gene that codes for DNA repair activity that removes the oxidatively-damaged base 8-oxoguanine from DNA. The mouse ogg1 complements a bacterial defect in 8-oxoguanine repair and that its protein product removes 8- oxoguanine from DNA in vitro. This proposal describes transgenic and gene targeting strategies that can be used to establish the role of ogg1 in protecting mice from the effects of oxidative stress. Strains that over-express ogg1 will be used to explore the protective effects of the ogg1 protein. Mice lacking the gene will be examined systematically for any pathological changes. The effects of endogenous and exogenous oxidative processes in mice that overexpress or lack ogg1 will be measured. The effects of altering the level of ogg1 gene expression on the rate of mutagenesis and tumorigenesis also will be determined.
