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

RUI：DNA 损伤 8-Oxo-2-脱氧鸟苷生物活性的化学研究

• 批准号: 1903855
• 负责人: Michelle Hamm
• 金额: $ 27万
• 依托单位: University of Richmond
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1903855&HistoricalAwards=false
• 关键词: RUI; Chemical; Investigations; into; Bioactivity

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.

DNA受到各种环境因素的持续攻击，其中许多可能会导致DNA损伤。氧化损伤是由DNA和活性氧之间的反应引起的，这些反应是由辐射，化学致癌物甚至作为食物消耗的一部分产生的。 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中存储的信息的变化），可能导致衰老和包括癌症在内的各种疾病。有了这一奖项，化学司的化学过程计划是为主要是本科机构的里士满大学的米歇尔·哈姆（Michelle Hamm）博士提供资金，以研究由氧化损坏的DNA引起的突变的化学基础。研究产生的新知识可深入了解DNA损伤与引起的生物学问题之间的联系。这项研究还允许本科生和学士后的学生学习化学和/或生化实验室技术，以及在他们攻读研究生或专业学校或加入21世纪STEM员工时对他们有用的其他技能。该项目侧重于DNA病变8-oxo-2'-脱氧鸟苷（ODG），并使用ODG或2'-脱氧鸟苷（DG）的结构类似物来探测影响ODG或ITS 5'- triphosphate类似物ODGTP，ODGTP的空间和/或电子特性。一组目标集中在ODG或ODGTP和四个人类跨性别聚合酶之间的相互作用上。通过比较合成类似物的聚合酶反应效率与DG/DGTP，ODG/ODGTP以及彼此之间，可以分离影响ODG和ODGTP诱变潜力的确切原子因子。该项目的另一个主要目的包括使用细菌孵育和下一代测序，以更好地了解ODG诱变和体内修复。通过将ODG的突变率与各种细菌细胞菌株中的类似物的突变率进行比较，包括ODG修复缺陷的突变率，可以确定导致其细菌突变率的ODG基础内的重要特性和位置。这奖可以反映NSF的法定任务，并通过使用基础的智力效果和广泛的范围来评估支持，并以评估的评估值得评估。