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

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DNA is under constant attack by various environmental factors, many of which can cause DNA damage. Oxidative damage arises from reactions between DNA and reactive oxygen species that are produced by radiation, chemical carcinogens, or even as part of food consumption. Oxidative damage is one of the most common types of DNA damage in mammalian cells and can also cause mutations (a change in the information stored in DNA), potentially leading to ageing and various diseases, including cancer. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Michelle Hamm from the University of Richmond, a primarily undergraduate institution, to investigate the chemical basis of mutations caused by oxidatively damaged DNA. The new knowledge generated by the research provides insight into the link between DNA damage and the biological problems that it causes. The research also allows undergraduate students and a post-baccalaureate student to learn chemical and/or biochemical laboratory techniques, as well as other skills that will be useful to them as they pursue graduate or professional school or join the 21st century STEM workforce. This project focuses on the DNA lesion 8-oxo-2'-deoxyguanosine (OdG) and uses structural analogues of OdG or 2'-deoxyguanosine (dG) to probe the steric and/or electronic properties that affect the bioactivity of OdG or its 5'-triphosphate analogue, OdGTP. One set of aims focuses on the interaction between OdG or OdGTP and four human translesion polymerases. By comparing polymerase reaction efficiencies of the synthesized analogues to dG/dGTP, OdG/OdGTP, and each other, the exact atomic factors that influence the mutagenic potential of OdG and OdGTP can be isolated. The other main aim of the project includes the use of bacterial incubation and next generation sequencing to better understand OdG mutagenesis and repair in vivo. By comparing the mutation rates of OdG to that of its analogues in various bacterial cell strains, including those that are OdG repair deficient, the important properties and positions within the OdG base that lead to its bacterial mutation rate can be identified.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.