The information held within the DNA blueprint for life can be eroded by damage to DNA bases due to cellular metabolism and environmental exposures. Modified DNA bases lead to changes in the DNA sequence called mutations. These mutations can negatively impact cellular processes but they can be corrected by the action of DNA repair enzymes. 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 uncover molecular details of how damaged DNA bases are detected and repaired. The research makes uses of synthetic DNA chemistry and X-ray crystallography to trap and visualize steps in the DNA repair process that are otherwise too fleeting to study and to generate a detailed molecular picture of the DNA repair process. Graduate and undergraduate students learn how to combine different chemistry and biology approaches to reveal and understand key features of fundamental life processes. This project is also integrated into a unique "Course-Based Research Experience" (CURE) laboratory course taught at both the University of California Davis and the University of Utah. Undergraduates emerge from the course with improved critical thinking skills and a better conceptual knowledge of how information crucial for living organisms is encoded in their DNA and maintained by DNA repair enzymes.
This research project delineates chemical mechanisms of base excision repair (BER) glycosylases to illuminate how these enzymes efficiently find rare modified DNA bases. Modified nucleotides that mimic transition states are prepared through synthetic chemistry. Structural studies of several BER glycosylases bound to DNA containing these transition state mimics provide insight into the catalysis of base excision. Indeed, surprising features uncovered with three BER glycosylases, namely MutY, AlkD and MBD4, raise new questions on these and related glycosylases and prompt new innovative structural and functional studies that will be pursued by the David and Horvath research groups. Students working on this project receive interdisciplinary training spanning synthetic nucleic acid chemistry, nucleic acid enzymology, and DNA-protein crystallography. Fostering environments in which women and minority students thrive is a core goal of the work supported by this award. This project has a positive broader educational impact because it is tied to two undergraduate laboratory courses that introduce incoming and advanced undergraduate students to modern research techniques and approaches used in chemical biology with a focus on DNA damage and repair.
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.
