Collaborative Research: Chemical Biology of DNA repair

University Of Utah, Salt Lake City UT

Investigators

Abstract

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.