The overall goal of this research program is to elucidate, at the molecular level, the biological processing and consequences of free radical-induced DNA lesions produced by normal oxidative metabolism, the radiolysis of water, and a variety of chemical pollutants. These lesions constitute the preponderant class of cellular DNA damages and are removed by base excision repair. An unrepaired DNA lesion may block replication casing cellular cytotoxicity or may direct incorporation of an incorrect base leading to mutagenesis. Thus, the biological fate of the damaged cell depends upon the efficiency of repair and the interaction between the lesion and the replication apparatus. To examine the molecular processing of free radical-induced DNA damage, this laboratory has used the strategy of incorporating chemically synthesized model lesions into DNA substrates to study base excision repair in vivo, into templates for DNA synthesis in vitro to predict cytotoxicity and mutagenicity, and into biologically active transfecting DNA to confirm the in vitro predictions. The proposed studies specifically address the structural features of DNA lesions that putatively influence repair efficiency and mutagenic specificity, thus biological consequence and include cloning the genes for new and known enzymes involved in base excision repair processing. This work is driven by the hypothesis that unrepaired DNA lesions play a major role in carcinogenesis. This link is particularly relevant because free radical- induced damages are formed to such a large extent on a daily basis by metabolic oxygen that base excision repair enzymes are likely to be tumor suppressors. Accordingly, elucidating the enzymatic and biological processing of free radical-induced lesions should increase our understanding of the etiology of breast and other forms of human cancer.
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