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

通过这一瑞奖，生命过程化学项目支持里士满大学的米歇尔·哈姆教授更好地了解8-氧-2‘-脱氧鸟苷(ODG)及其5’-三磷酸衍生物OdGTP的立体和/或电子性质。氧化损伤的2‘-脱氧鸟苷衍生物ODG是最显著的DNA损伤之一，与衰老以及包括癌症在内的多种疾病有关。与DNA中只与2‘-脱氧胞苷(DC)碱基配对的2’-脱氧鸟苷(DG)不同，ODG可以与DC和2‘-脱氧腺苷(Da)配对，从而允许在复制过程中发生突变。HAMM小组在DG/dGTP和ODG/OdGTP之间的光谱上合成核苷酸类似物，并将这些核苷酸用于专注于这些有害核苷酸的复制和修复的生化实验。通过比较合成的类似物与DG/dGTP、ODG/OdGTP的酶活性，可以提出相应的假设，最终目的是建立ODG和OdGTP生物活性的分子基础。化学致癌物质、太阳辐射和正常新陈代谢过程都会产生活性氧。它们会破坏DNA并改变其携带的信息，可能会导致衰老和癌症等疾病。虽然这种损伤的总体影响已经很好地了解了，但导致观察到的影响的确切化学特性却更加难以捉摸。这项工作的目标是更好地了解一种最突出的氧化性DNA损伤背后的化学物质。这项研究将涉及以本科为主的本科院校的本科生，并提供拟议研究中使用的合成和生化技术方面的专门培训。研究人员还将学习重要的技能，包括时间管理、批判性思维、实验设计以及口头和书面交流。这些活动将为他们在高级水平上的进一步学习和在学术或工业环境中进行研究做好准备。

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.