The long-term goal of this research program is to understand the structural and mechanistic details of proteins involved in the life- and infection-cycles of disease-associated viruses.
Papillomaviruses are a family of small DNA viruses that infect epithelial cells causing both benign and malignant tumors. The best-studied strain is bovine papillomavirus type 1 (BPV-1), which causes fibropapillomas in cows. More than 70 human papillomaviruses (HPV) have been characterized and classified based on evolutionary relationships and the pathology of the viral lesions. Among the strains associated with mucosal lesions, the low-risk strains (e.g. HPV-6, and -11) cause skin and ano-genital warts. High-risk strains (HPV-16, -18, -31, -33) are associated with neoplasias that can progress to malignancies, most commonly cervical cancer.
Our studies investigate critical regulatory events in the life cycle of the cancer-associated papillomaviruses. We have determined the three-dimensional structures of the DNA binding domains of the transcription and replication regulatory E2 protein from human papillomavirus strains 16 and 18, as well as bovine papillomavirus strain 1, free and bound to DNA. In parallel functional studies, we have defined the role of DNA conformation in the ability of the E2 proteins to recognize and bind to specific sites on the papillomavirus genome. These studies not only enhance our understanding of the life- and infection-cycles of an important human pathogen, but also provide a foundation for the design of therapeutic strategies.