Collaborative Research: Chemical Biology of DNA repair

在化学系生命过程化学项目的支持下，加州大学戴维斯分校的希拉·大卫和犹他大学的马丁·霍瓦斯正在合作研究DNA的修复。DNA不断受损，DNA修复对生命至关重要。现在已经很好地理解碱基切除修复(BER)糖基酶是一线酶，它能够找到具有微小损伤的稀有DNA碱基，并启动这些碱基的修复。然而，目前还不清楚这些非凡的酶是如何在分子和化学水平上发挥作用的。该项目将应用化学生物学方法来揭示DNA修复酶MutY、OGG1和内切酶III(EndoIII)的机制，这些酶具有相似的结构和共同的祖先蛋白。通过该项目获得的发现对生物技术和医学具有影响和潜在的应用。研究活动将为研究生和本科生提供培训机会，旨在促进发展一支包容和多样化的STEM(科学、技术、工程和数学)劳动力队伍。该项目将被整合到两所大学的教育项目中，以提供真实的科学研究体验。进一步的广泛影响将包括项目参与者充当科学大使的外联计划，他们将科学家和非科学家联系起来，重建对科学的信任。这项工作的一个重要元素是使用过渡态(TS)模拟来提供对化学机制的洞察，以及受损底物鉴定与碱基切除相结合的方式。具体地说，加州大学戴维斯分校/犹他州大学的合作团队将开发新的TS模拟药物，以测试与进化相关的BER糖基酶MutY、Endo III和hOGG1使用类似催化策略的想法。Davis/Horvath团队还将通过创建新的高通量分析来测试大型、多样化的MutY变体，从而描述MutY中对其搜索和救援机制的不同方面至关重要的主题。最后，这些创新方法的进一步发展将被用来创造基于BER糖基酶的新的化学生物学工具来操纵活的有机体中的DNA。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes program in the Division of Chemistry, Sheila David from the University of California, Davis, and Martin Horvath from the University of Utah are collaborating to study the repair of DNA. DNA is constantly damaged, and DNA repair is essential for life. It is now well understood that base excision repair (BER) glycosylases are the front-line enzymes that competently find rare DNA bases with subtle damage and initiate repair of these bases. However, it is unclear how these remarkable enzymes work at the molecular and chemical level. The project will apply a chemical biology approach to reveal insight into the mechanisms of the DNA repair enzymes MutY, OGG1 and endonuclease III (EndoIII), BER glycosylases that share structural similarity and a common ancestral protein. The discoveries obtained through this project has implications for and potential applications in biotechnology and medicine. The research activities will provide training opportunities for graduate and undergraduate students with the intention to contribute to the development of an inclusive and diverse STEM (science, technology, engineering and mathematics) workforce. The project will be integrated into education programs at both universities to provide an authentic science research experience. Further broad impacts will include outreach programs with project participants acting as Science Ambassadors who connect scientists and nonscientists and rebuild trust in science.A significant element of this work is the use of transition state (TS) mimics to provide insight into chemical mechanisms and the ways in which damaged substrate identification is coupled to base excision. Specifically, the collaborative UC-Davis/Utah team will develop new TS mimics to test the idea that the evolutionarily-related BER glycosylases MutY, Endo III and hOGG1 use similar catalytic strategies. The Davis/Horvath team will also delineate motifs in MutY that are critical for distinct facets of its search and rescue mechanism by creating new high-throughput assays to test large, diverse sets of MutY variants. Lastly, further development of these innovative methods will be leveraged to create new chemical biology tools based on BER glycosylases to manipulate DNA in living organisms.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.