We explore mechanistic problems at the intersection of biochemistry, cell biology, and human disease.
Enzymes running in reverse: the role of IDH mutation in cancer
Enzyme dysfunction can result from mutation, misregulation, and amplification, which can lead to cancer and other diseases. Using kinetic, structural, and cellular based methods, we can understand how catalysis is altered upon enzyme mutation. One focus is elucidating the catalytic pathway and structural features of isocitrate dehydrogenase (IDH) mutations implicated in gliomas and leukemia. Some IDH mutations have the potential to confer both oncogenic and tumor suppressive properties, and can even result in generation of a novel oncometabolite product. This hints that intriguing and complex catalytic and structural alterations must be at work. A mechanistic understanding of how these mutations change enzyme function provide a critical foundation for understanding cancer.
Exploring mechanisms of genome (in)fidelity
Polymerases and cancer: Maintaining the integrity of the human genome is an enormous challenge during DNA replication. Mutations can alter the activity of human polymerases, which in turn can lead to cancer and rare congenital diseases. Importantly, proposed tumor suppressing mutations in A and B family DNA polymerases have the potential to lead to disease through vastly different mechanisms, including changing rates of polymerization or altering fidelity, and these mechanisms in turn can use a variety of approaches to achieve these devastating outcomes. We are interested in exploring the molecular mechanisms of physiologically important polymerase mutations and identifying the downstream affects on DNA damage and repair. This will help provide tools for understanding disease mechanisms and assessing DNA damage repair pathways as therapeutic targets.
We are also interested in exploring the molecular mechanisms of replication and fidelity of viral polymerases. Therapeutically targeting viral polymerases has been enormously successful in combating infections such as HIV and hepatitis C. In collaborative work, we are interested in exploring the catalytic and structural features of the RNA polymerase from Zika virus and to identify strategies for therapeutic inhibition.