Collaborative Research: Chemical Biology of DNA repair

合作研究：DNA修复的化学生物学

• 批准号: 2204228
• 负责人: Sheila David
• 金额: $ 45.67万
• 依托单位: University of California-Davis
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2204228&HistoricalAwards=false
• 关键词: Collaborative; Research; Chemical; Biology; DNA

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.

在化学系生命过程化学项目的支持下，来自加州大学戴维斯分校的希拉大卫和来自犹他州大学的马丁·霍瓦特正在合作研究DNA的修复。DNA不断受到损伤，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）糖基化酶是能够发现具有细微损伤的罕见DNA碱基并启动这些碱基的修复的第一线酶。然而，目前还不清楚这些非凡的酶如何在分子和化学水平上发挥作用。该项目将应用化学生物学方法来揭示DNA修复酶MutY，OGG 1和内切核酸酶III（EndoIII），BER糖基化酶的机制，这些酶具有结构相似性和共同的祖先蛋白质。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，旨在促进包容性和多样化的STEM（科学，技术，工程和数学）劳动力的发展。该项目将被整合到两所大学的教育计划中，以提供真实的科学研究体验。更广泛的影响将包括项目参与者作为科学大使的外展计划，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组成部分是使用过渡态（TS）模拟物来深入了解化学机制以及受损底物识别与碱基切除相结合的方式。具体来说，加州大学戴维斯分校/犹他州的合作团队将开发新的TS模拟物，以测试与进化相关的BER糖基化酶MutY、Endo III和hOGG 1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检测方法来测试大量不同的MutY变体，从而描绘MutY中对其搜索和救援机制的不同方面至关重要的基序。最后，这些创新方法的进一步发展将被用于创建基于BER糖基化酶的新化学生物学工具，以操纵活生物体中的DNA。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。