BIOLOGY SEMINAR -- CANCELED

Oxidative DNA damage have been postulated to be major type of endogenous damage leading to human degenerative disorders including cancer, cardiovascular disease and brain dysfunction. Despite the progress in understanding of the base excision repair (BER) pathway it is still unclear why mice deficient in DNA glycosylases that remove oxidized bases are not sensitive to oxidizing agents. Therefore, we investigated whether an alternative nucleotide incision repair (NIR) pathway may serve as back up system to BER to cleanse genomic DNA of potentially mutagenic and cytotoxic lesions. Recently, we attempted to elucidate the role of the NIR and 3'-5' exonuclease activities of AP endonucleases in handling cytotoxic DNA lesions and and preventing 8oxoG-induced mutagenesis in E. coli and S. cerevisiae. We have shown that AP endonucleases can remove oxidized nucleotides at 3'-termini of a gap or a nick. Consistent with this, the yeast Apn1 strongly suppresses the rate of G•C to T•A transversions in the ogg1 mutants. Furthermore, we reported a mutational separation of various DNA repair functions of the E. coli Nfo which revealed the biological function of the NIR pathway. We extended data obtained on bacteria to human cells showing that the intranuclear environment of human cells is compatible with Ape1-catalyzed NIR activity. These findings further substantiate a role of the NIR pathway in the removal of oxidative DNA damage that, when left unrepaired, induces cell death and mutagenesis.