With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Sheila David at The University of California - Davis and Dr. Martin Horvath at The University of Utah to investigate how DNA damage is detected and repaired. DNA is the blueprint for life, and damage to this molecule caused by cellular metabolism or by environmental hazards can lead to mutations, cell death or changes in the blueprint over the course of evolution. The preservation of DNA relies on the action of DNA repair enzymes. Despite years of work that has uncovered DNA repair enzymes and the types of damage upon which they act, mysteries remain as to how these amazing enzymes work at the chemical level. This project uses synthetic DNA chemistry and X-ray crystallography to trap and visualize steps, in the DNA repair process, that are otherwise too fleeting to study. This strategy provides a detailed molecular picture of the DNA repair process. The project applies a multi-faceted approach to investigate several enzymes that specialize in repairing damaged DNA bases. Graduate and undergraduate students involved in this project are receiving training in synthesis, biochemistry and X-ray crystallography. The discoveries and results produced by this project are being incorporated into a DNA damage and repair undergraduate laboratory class at UC Davis and at the University of Utah. Undergraduate students in these courses will emerge with skills in critical thinking and conceptual knowledge related to how the information of life is encoded in DNA and maintained by DNA repair enzymes.
This research project delineates chemical mechanisms of base excision repair (BER) glycosylases and illuminates how these enzymes efficiently find rare modified DNA bases. Modified nucleotides that mimic transition states are being prepared through synthetic chemistry. Structural studies of several BER glycosylases bound to DNA containing these transition state analogs are revealing the strategies used by these enzymes to catalyze base excision. Preliminary work has revealed several surprising features of the BER glycosylases MutY and AlkD, and prompted novel structural and mechanistic studies on these and related BER glycosylases. This project is revealing common themes and unique features in the chemistry underlying DNA repair.
