The genetic information held in DNA molecules is copied each time a cell divides. Highly efficient and accurate enzymes called DNA polymerases carry out this important copying (replication) function. Research in my lab is directed at determining how DNA polymerases copy DNA with high fidelity. It is important to understand the mechanism of DNA replication because aberrant replication can result in mutations that contribute to the development of human diseases such as cancer and to aging. DNA replication is also a target of anti-viral and anti-bacterial drugs, but drug-resistance is a problem; our studies are shedding light on mechanisms that promote drug sensitivity and resistance.
We are using the power of yeast genetics to study DNA replication in vivo in Saccharomyces cerevisiae . Genetic tools are also used to study the bacteriophage T4 DNA polymerase, which is a useful model for learning about eukaryotic DNA polymerases. Highly sensitive fluorescence assays have been developed to study DNA polymerase function in vitro . The combination of genetic and biochemical approaches has been rewarding. We have discovered new insights into how DNA polymerases bind nucleotides and certain drugs and we have identified critical steps in the proofreading pathway, which is a mechanism that allows DNA polymerases to remove misincorporated nucleotides. In addition, information learned from our DNA polymerase studies is being applied to the development of novel DNA sequencing methods.