Faculty Appointments
Professor of Biochemistry
Professor of Pathology, Microbiology and Immunology
Education
Ph.D., Molecular and Cellular Biology, Brandeis University, Waltham, MassachusettsM.S., Biochemistry, Brandeis University, Waltham, MassachusettsB.S., Biochemical and Biophysical Sciences, University of Houston, Houston, Texas
Research Description
My research program has two branches: 1) investigating the molecular underpinnings of the conflicts between the replication and transcription machineries, and 2) identifying and inhibiting of mutagenesis mechanisms that drive drug resistance development.
The focus of the first branch is to determine the impact of replication-transcription conflicts on DNA replication, mutagenesis, and evolution, and determining how cells overcome this problem. Over the years, we have made major breakthroughs in this area, including: (i) identifying the critical factors that make conflicts detrimental, (ii) determining that conflicts induce replisome disassembly multiple times every cell cycle, (iii) showing that conflicts have a powerful impact on the evolution of genome architecture. (iv) demonstrating that conflicts promote temporally and spatially-controlled evolution. The last discovery mentioned was arguably one of our most impactful findings given that it was the first mutagenesis mechanism described that promotes evolution in a gene- specific, and expression-dependent manner, exactly at the time when adaptation is critical.
The focus of the second branch is on the mechanisms that promote drug resistance which is a serious problem both in the context of infections and cancer treatment. Although many groups are working on developing new treatments that kill cells to resolve this problem, history has shown that drug resistance arises regardless of the nature or potency of the treatments administered to patients. We are working on resolving the problem by inhibiting the key driver of drug resistance development; mutagenesis and subsequent evolution. Over the years, we have focused on bacterial pathogens and have identified key molecular mechanisms that promote evolution of antimicrobial resistance. We have identified compounds that inhibit the function of one of these proteins (Mfd), which we are now developing for use in the clinic as a means to prevent resistance development during treatment of infections. As we continue this work, we are now expanding our research to mammalian systems, and identifying factors that drive mutagenesis and evolution in cancer cells.
The focus of the first branch is to determine the impact of replication-transcription conflicts on DNA replication, mutagenesis, and evolution, and determining how cells overcome this problem. Over the years, we have made major breakthroughs in this area, including: (i) identifying the critical factors that make conflicts detrimental, (ii) determining that conflicts induce replisome disassembly multiple times every cell cycle, (iii) showing that conflicts have a powerful impact on the evolution of genome architecture. (iv) demonstrating that conflicts promote temporally and spatially-controlled evolution. The last discovery mentioned was arguably one of our most impactful findings given that it was the first mutagenesis mechanism described that promotes evolution in a gene- specific, and expression-dependent manner, exactly at the time when adaptation is critical.
The focus of the second branch is on the mechanisms that promote drug resistance which is a serious problem both in the context of infections and cancer treatment. Although many groups are working on developing new treatments that kill cells to resolve this problem, history has shown that drug resistance arises regardless of the nature or potency of the treatments administered to patients. We are working on resolving the problem by inhibiting the key driver of drug resistance development; mutagenesis and subsequent evolution. Over the years, we have focused on bacterial pathogens and have identified key molecular mechanisms that promote evolution of antimicrobial resistance. We have identified compounds that inhibit the function of one of these proteins (Mfd), which we are now developing for use in the clinic as a means to prevent resistance development during treatment of infections. As we continue this work, we are now expanding our research to mammalian systems, and identifying factors that drive mutagenesis and evolution in cancer cells.
Research Keywords
DNA replication, replication-transcription conflicts, mutagenesis, pathogenesis, drug resistance