Mechanistic studies of radical-induced DNA damage

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The formation of DNA damage by ionizing radiation, photosensitization, oxygen and nitrogen free radicals, and certain chemicals involves the generation of organic radicals centered on DNA components. These radicals give rise to unstable and stable diamagnetic products, commonly referred to as DNA damage. Much of our knowledge about DNA damage is based on studies in which monomers are exposed to radical generating systems such as ionizing radiation. However, it is clear today that the reaction of primary damaging species and the fate of subsequent organic radicals are greatly affected by DNA sequence and secondary structure. My long term research program targets the characterization of DNA damage and the elucidation of mechanisms leading to the formation of damage. The goal of my research program over the next 5 years is to advance our basic knowledge on the chemistry of two important families of radicals generated by the exposure of DNA to ionizing radiation (i.e., x-rays, gamma-rays, charged particles), and other oxidizing and reducing agents. One family includes nitrogen centered radicals of DNA bases containing an exocyclic amino group (adenine, cytosine, 5-methylcytosine). These radicals arise from either the direct ionization of DNA or the reaction of highly reactive hydroxyl radicals. The other family includes radicals generated by the reaction of low energy electrons (0-30 eV) that are ejected during the direct ionization of molecules. To accomplish my specific goals I will (a) synthesise novel photoactive derivatives of DNA bases, (b) characterize the full spectrum of modifications in irradiated DNA containing these derivatives, using chromatography and mass spectrometry, and investigate the effects of DNA structure on the formation of products. These studies will greatly increase our most fundamental knowledge of radical-induced DNA damage, facilitate our ability to study DNA repair and mutagenesis, as well as contribute to the discovery of biomarkers of DNA damage that will allow us to assess the genetic consequences of toxic agents and drugs.