Janice D. Pata, Ph.D.

Genome replication is a fundamentally important process in all cells and viruses. Mistakes made during replication cause mutations as well as large scale genome rearrangements, which can ultimately cause antibiotic resistance in bacteria as well as aging, cancer and resistance to chemotherapy in humans. Cells contain multiple polymerases, yet our understanding of how all these enzymes contribute to genome stability is far from complete.

Of particular interest is how the DNA polymerases that are responsible for the majority of genome duplication are replaced by the more specialized polymerases that are responsible for translesion synthesis across from damaged DNA bases. While the translesion polymerases help cells tolerate DNA damage, they have a 10- to 1000-fold higher error rate than replicative polymerases and can substantially increase the frequency of mutations. The situation is made even more complex since most cells have multiple translesion polymerases, each with their own lesion-bypass and mutational specificities. Genome stability is thus critically dependent on which polymerase carries out DNA synthesis.

Our main research focus is on the replicative and translesion polymerases of Staphylococcus aureus, which is responsible for appoximately 300,000 antibiotic-resistant infections and 10,000 deaths every year in the United States. We characterize the relationships between the structure and biochemical activity of these polymerases using X-ray crystallography, pre-steady-state enzyme kinetics and site-directed mutagenesis and follow the evolution of antibiotic resistance in a model bioreactor system that recapitulates clinically relevant mutations identified in patients. Our goal is to identify new strategies for combating these infections.

We also have active collaborations with Dr. Alex Ciota to study the error-prone RNA genome replication of flaviviruses and with Drs. Kathleen McDonough and Haixin Sui to study transcriptional regulation in Mycobacterium tuberculosis.