The broad long-term objective of this research proposal is to continue our investigation of nitric oxide (NO)-induced oxidative DNA damage in bacterial and transgenic mammalian cells. It has been established that NO, acting alone or in combination with reactive oxygen species (ROS), can induce DNA damage and mutagenesis in various cells. The proposed research plan will involve (a) molecular analysis of NO-induced mutations in the transgenic mammalian G12 cell line, using polymerase chain reaction (PCR) and DNA dideoxy sequencing; (b) measurement of oxidative DNA damage in bacterial and G12 cells using high performance liquid chromatography and electrochemical detections (HPLC/EC); and (c) assessment of NO-induced DNA damage and repair in G12 cells using the single cell gel electrophoresis (SCGE) assay, also known as the Comet assay. Intensive investigation of NO-induced DNA damage in the last decade has revealed differences between the ubiquitous molecule NO and certain ROS, most notably hydrogen peroxide (H202). The central hypothesis to be tested is that NO-induced oxidative damage is different from H2O2-induced oxidative damage. This will be tested by demonstrations that different bases become damaged by NO vs. H2O2, and that this damage is modulated by different cellular factors. The significance of this research lies in its comprehensive approach to determine the potentially broad range of genomic effects of NO. Our approach will allow us to evaluate variations, similarities, as well as synergism in oxidative DNA damage that may exist among chemicals known to be NO-donors or H2O2- generators.
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