The overall goal of the proposed research is to probe the fundamental reaction mechanisms of radical mediated nucleic acid damage. Many of the issues addressed are derived from observations made using ionizing radiation as an agent for inflicting damage on nucleic acids. A significant portion of our effort is focused on elucidating the reactivity of nucleobase radicals, because their generation is unique to ionizing radiation, and their involvement in strand damage is uncertain. The general approach involves the independent generation of reactive intermediates that are involved in nucleic acid damage from synthetic precursors.
Specific aims i nclude: 1. Investigation of nucleic acid damage amplification via: a. The transposition of spin from nucleobase radicals to the sugar of adjacent nucleotides. b. The loss of superoxide (and its subsequent transformation into hydroxyl radical) from peroxyl radicals derived from nucleoside radicals. c. Investigation of the production of bistranded lesions via interchain hydrogen atom transfer and/or the generation of diffusible reactive species from primary nucleic acid lesions. 2. Elucidation of the mechanism by which 5-bromodeoxyuridine sensitizes nucleic acids to strand damage. 3. Determination of the role of sugar radicals formed via abstraction of hydrogen atoms from C1' of nucleosides in nucleic acid damage. 4. Examination of the effects of radiosensitizers on the chemistry of a nucleobase radical intermediate. Increased understanding of these molecular processes is useful to understanding the association between nucleic acid damage and the etiology of diseases. Furthermore, the potential discovery of novel nucleic acid damage mechanisms can provide the impetus for the design of new therapeutic agents.
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