David J. Segal, Ph.D.

Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ 85721

How can we use the information in the human genome to improve human health? The Cys2-His2 type zinc finger domain is one of the most abundant structural motifs found in nature. Their most famous role is in sequence-specific DNA binding, though others mediate interactions with RNA or proteins. Using the combined approaches of bioinformatics, proteomics, X-ray crystallography, computer modeling, and biochemistry, we are revealing nature's purpose for encoding 4,500 zinc finger domains into our genome. By understanding what they do and how they do it, we can then exploit their abilities to produce new targeted molecular tools and therapeutics. In previous work, we have used randomization and phage-display selection methods to design proteins that can recognize new DNA sequences. This technology has been used to create artificial transcription factors that can up- and down-regulate endogenous genes. Current work aims to engineer targeted DNA endonucleases, retroviral integrases, and sequence biosensors. These reagents are being applied in the study and treatment of diseases such as cancer and HIV/AIDS.