Dr. Sheila S. David
Research Summary
The central aim of my research program has been to provide information on the molecular basis for DNA damage recognition and repair mediated by base excision repair (BER) glycosylases. BER glycosylases mediate the repair of chemically modified DNA bases which is a fundamental process in all forms of life to preserve DNA integrity. DNA repair, and BER specifically, are of high human health relevance in the etiology of cancer and have emerged as exciting new therapeutic targets. The goals of my research program are to provide detailed insight into specific types of BER glycosylases and to develop new chemical approaches for investigating DNA repair enzymes. To meet these goals, we have creatively paired enzymology, nucleic acid chemistry, structural methods and cellular assays. My program has focused heavily on a unique bacterial BER glycosylase, MutY and its human homolog MUTYH. These unusual Fe-S enzymes remove adenine from OG:A mispairs (where OG refers to 8-oxo-7,8-dihydro-guanine, a common oxidation product of guanine) as the first step in initiating repair and preventing mutations associated with OG. My laboratory played a key role in establishing the direct link between inherited variations in MUTYH and colorectal cancer (CRC), a CRC-mechanism now referred to as MUTYH-associated polyposis (MAP). This ground-breaking discovery has significantly impacted the directions of my research and the field of DNA repair. We have also leveraged chemical biology approaches to study the human Nei-like (NEIL) family of BER glycosylases, providing surprising new insights, such as the novel link to RNA editing.
“Dr. Beckman touched my scientific life in so many ways! I first met Dr. Beckman when he was visiting Caltech when I was a postdoctoral associate with Jackie Barton (in the early 90s). He was touring the newly established Beckman Institute and I was one of the lucky postdocs who got to be in the brand new space. Dr. Beckman told several jokes and was so enthusiastic about our work, it was a great experience. I also met him several times as a BYI. I fondly remember him slipping money to Harry Grey for the BYIs to go out drinking. Those were special times! The project I originally pitched to the Beckman Foundation has been my career long focus. I appreciate the foundation seeing that there was important and creative ideas in my proposal! Thanks for that early support-- it makes an incredible difference.