Associate Professor of BacteriologyAddress: 1550 Linden Drive, Room 6478
Phone: (608) 263-0307
Lab Phone: (608) 263-1072
Accurate DNA replication is essential for the survival and fitness of all organisms. The goal of my research is to characterize the multifaceted interface between DNA replication and other cellular processes. Through this interface, replication responds readily to metabolic and external cues; conversely, cells monitor the replication status and respond accordingly. Components of this interface are likely to play paramount roles in the maintenance of genome stability and prevention of genetic diseases and cancer. Because replication mechanisms are conserved across all of life, our work in bacteria is a broadly applicable model. We currently focus on three major directions:
Prevention of transcription/replication conflict. There is a genome-wide conflict between replication and transcription, with important consequences to cellular fitness and genome integrity. Bacteria have developed diverse mechanisms to deal with this conflict. The conflict between replication and transcription can be prevented by a genome-wide strand bias to encode genes in the leading strand. In addition, a functional analog of the eukaryotic transcription factor TFIIS is crucial for prevention of this conflict. Our discoveries laid the foundation for addressing the following questions: How do transcription factors prevent the conflict between transcription and replication? What is the physical nature of the transcription barrier and how it is formed in response to stress? What are the evolutionary consequences? We are combining biochemical, genetic and genomic approaches to answer these questions.
The interface between DNA replication and the cellular environment. We are testing the hypothesis that multiple small molecules, induced by a spectrum of stresses, regulate DNA replication robustly. Our previous discovery of a novel regulatory mechanism of replication elongation by a small molecule, (p)ppGpp, established such a precedent. We are currently investigating the molecular mechanism of this regulation and expanding this theme to include a spectrum of other small molecules and protein regulators.
The physiological role of the nucleotide (p)ppGpp in stress response. (p)ppGpp is ubiquitously present in bacteria and is crucial for their survival and virulence. How (p)ppGpp ensures survival of Gram-positive bacteria upon stress remains elusive. We had made progress in finding answers to this question. We have identified components of (p)ppGpp metabolism aided by whole-genome sequencing. Taking advantage of this knowledge and applying genetic and genomic methods, we are building a new model of (p)ppGpp function.