Mechanisms of Nucleic Acid Oxidation and Cross-linking

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The Organic and Macromolecular Chemistry Program supports Professor Cynthia J. Burrows at the University of Utah who proposes to explore mechanistically how DNA-protein crosslinks arise during the course of oxidative damage. Oxidative insult to chromatin leading to formation of DNA-protein crosslinks is poorly understood at the molecular level. Studies outlined in the proposal build on recent results showing that 8-oxo-7, 8-dihydroguanosine is sensitive to further oxidation by one-electron oxidants leading to a quinonoid intermediate that is nucleophilically trapped to ultimately generate hydantoin products. Methods will be developed to understand the chemical structures responsible for DNA-protein crosslinking via both DNA oxidation and protein oxidation. Professor Burrows hopes to formulate a detailed molecular picture of how DNA is oxidized in the presence of reactive species such as protein and polyamine nucleophiles.The Organic and Macromolecular Chemistry Program supports Professor Cynthia J. Burrows who will train undergraduate, graduate, and postdoctoral students to be well versed in mechanistic organic chemistry. These students will also gain biotechnical skills in the manipulation of nucleic acids and proteins and contribute to our molecular understanding of DNA damage, which underlies processes leading to aging, cancer, and neurological disorders. In addition, Professor Burrows' laboratory will continue to serve as a resource to faculty members at 4-year institutions to collaborate on projects in nucleic acid chemistry and to provide mass spectrometry expertise to assist these collaborations.