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

DNA不断受到各种环境因素的攻击，其中许多因素会导致DNA损伤。氧化损伤是DNA与辐射、化学致癌物、甚至食物消费中产生的活性氧物种之间的反应造成的。氧化损伤是哺乳动物细胞中最常见的DNA损伤类型之一，也可能导致突变(DNA中存储的信息发生变化)，可能导致衰老和包括癌症在内的各种疾病。通过这一奖项，化学系的生命过程化学项目资助里士满大学的Michelle Hamm博士研究氧化损伤DNA引起突变的化学基础。这项研究产生的新知识为深入了解DNA损伤及其引起的生物问题之间的联系提供了洞察力。这项研究还允许本科生和毕业后的学生学习化学和/或生化实验室技术，以及其他对他们攻读研究生或专业学校或加入21世纪STEM劳动力有用的技能。本项目以DNA损伤8-氧-2‘-脱氧鸟苷(ODG)为研究对象，利用ODG或2’-脱氧鸟苷(DG)的结构类似物来探索影响ODG或其5‘-三磷酸类似物OdGTP生物活性的空间和/或电子性质。一组AIMS专注于ODG或OdGTP与四种人类跨损伤聚合酶之间的相互作用。通过比较合成的类似物与DG/dGTP、ODG/OdGTP以及它们之间的聚合反应效率，可以分离出影响ODG和OdGTP诱变潜力的确切的原子因素。该项目的另一个主要目标包括使用细菌培养和下一代测序来更好地了解ODG在体内的突变和修复。通过比较ODG与其类似物在各种细菌细胞株中的突变率，包括那些ODG修复缺陷的细菌株，可以确定导致其细菌突变率的ODG碱基中的重要属性和位置。这一奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.