Thomas J. Kelly, MD, PhD

The long-term interest of my laboratory is to understand how the cellular genome is duplicated during the cell cycle. In the course of growth and division, eukaryotic cells duplicate their genomes with remarkable fidelity. The precision of this process depends in large measure upon stringent regulatory mechanisms that couple DNA replication to cell cycle progression. Initiation must be triggered at the appropriate time in the cell cycle at many hundreds or thousands of separate sites (origins of DNA replication) in the parental chromosomes. However, initiation must be prevented at these same sites in the newly synthesized daughter chromosomes. These controls ensure that each DNA segment in the genome is duplicated in a timely fashion exactly once each cell cycle.

Additionally, DNA replication must be coordinated with the other events of the cell cycle, such as mitosis and cell division. This coordination is achieved by regulatory mechanisms that enforce the strict alternation of DNA replication and mitosis. Finally, eukaryotic cells have evolved supplementary controls, called “checkpoints,” that alter the normal course of cell cycle progression in response to potentially genotoxic events, such as DNA damage or perturbations of DNA synthesis. These and other regulatory mechanisms function together to maintain the integrity of the genome during the replication process.

My laboratory studies the regulation of chromosome replication in both mammalian cells and in the fission yeast, Schizosaccharomyces pombe, which shares many properties with higher eukaryotes. We make use of both genetic and biochemical approaches to address the following questions.

• What are the structural and functional characteristics of origins of DNA replication in eukaryotic chromosomes?
• What are the genes/proteins required for initiation of DNA replication at S phase?
• How are the activities of these proteins controlled in the cell cycle by specific protein kinases and other regulatory factors?
• What mechanisms ensure that each origin of replication is activated only once each cell cycle?
• How is the timing of DNA replication coordinated with other major cell cycle events, such as mitosis? and
• How do “checkpoint” mechanisms alter initiation of DNA replication in response to DNA damage or other environmental perturbations?