The Enzymology of Replication

We work on projects that focus on elucidating the central principles that govern how cells and viruses reproduce their genetic record. Our approaches focus on the use of purified multi-enzyme systems, permitting manipulation of components in the absence of interfering pathways or degradative activities. Since DNA replication systems are highly conserved, our work with the E. coli replicase continues to help establish the salient features of replicases in all cells.

Our current work focuses on the mechanism of the ATP-powered assembly of the replicase on DNA, the mechanism of elongation and the coordination of the activities of the leading and lagging strand halves of the replicase with the helicase and other components present at the replication fork. We are also initiating investigations of how cells other than E. coli vary the central mechanistic theme for their own purposes. We are broadening our approaches to include structural and genetic approaches. Our studies of HIV currently focus on critical cellular activities required for viral replication. The goal is to understand the mechanism of retroviral replication and investigate possible cellular targets for chemotherapeutic intervention that cannot be evaded readily by viral mutation.