RUI: Chemical Investigations into the Bioactivity of the DNA Lesion 8-Oxo-2'-deoxyguanosine

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With this RUI Award, the Chemistry of Life Processes Program is supporting Professor Michelle Hamm of the University of Richmond to better understand the steric and/or electronic properties that dictate the bioactivity of 8-oxo-2'-deoxyguanosine (OdG) and its 5'-triphosphate derivative, OdGTP. The oxidatively damaged 2'-deoxyguanosine derivative OdG is one of the most prominent DNA lesions and has been linked to aging as well as several diseases including cancer. Unlike 2'-deoxyguanosine (dG) which base pairs only with 2'-deoxycytidine (dC) in DNA, OdG can pair with both dC and 2'-deoxyadenosine (dA), thus allowing for mutations during replication. The Hamm group synthesizes nucleotide analogues on the spectrum between dG/dGTP and OdG/OdGTP, and uses these in biochemical experiments focused on the replication and repair of these harmful nucleotides. By comparing the enzymatic activities of the synthesized analogues to dG/dGTP, OdG/OdGTP, and each other,one can put forth commensurate hypotheses with the ultimate goal of establishing the molecular basis for the bioactivity of OdG and OdGTP. Reactive oxygen species are created by chemical carcinogens, radiation from the sun, and normal metabolic processes. They can damage DNA and alter the information it carries, possibly leading to aging and diseases such as cancer. While the general effects of this damage are well understood, the exact chemical properties that lead to the observed effects have been more elusive. It is the goal of this work to better understand the chemistry behind one of the most prominent types of oxidative DNA damage. This pursuit will involve undergraduate students at a primarily undergraduate institution and provide specialized training in the synthetic and biochemical techniques used in the proposed studies. The researchers will also learn important skills including time management, critical thinking, experimental design, and verbal and written communication. These activities will prepare them for further study at an advanced level and for research in an academic or industrial setting.