My long-term interest 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.
Importantly, eukaryotic cells have evolved supplementary controls that come into play when DNA replication is perturbed by DNA damage. Under these circumstances cells trigger a complex array of pathways that alter cell cycle progression and activate DNA repair. These processes are critical for maintenance of the integrity of the genome and suppression of cancer.
I am using computational approaches to understand the dynamics of DNA replication in eukaryotic cells under normal and pathological conditions. My work builds upon an extensive body of biochemical studies of eukaryotic DNA replication carried out in my laboratory over several decades. I am interested in answering the following questions:
- What are the structural and functional characteristics of origins of DNA replication in eukaryotic chromosomes?
- What mechanisms control the timing of replication of different regions of the genome?
- What mechanisms account for the correlation of mutation rate with the timing of DNA replication in cancer cells?
- What mechanisms contribute to the generation of fragile sites and large scale rearrangements observed in cancer cells?