
Associate Professor of Microbiology & Immunology, and Biochemistry
Department of Microbiology and Immunology
Jacobs School of Medicine & Biomedical Sciences
DNA Replication, Recombination and Repair; Drug Discovery; Emergent Pathogens; Genome Integrity; Infectious Disease; Microbiology; Molecular and Cellular Biology; Molecular genetics; Virology
The primary focus of our research is understanding the mechanisms of DNA replication and how cellular DNA damage responses regulate DNA replication. Our primary focus is on small human DNA tumor viruses, polyomaviruses and papillomaviruses (HPV), although as these viruses hijack cellular DNA replication machinery and regulatory pathways, our work also has ramifications on cellular DNA replication and its regulation. As a result, our work has been leading to improved treatment approaches for HPV infections (unpublished work) as well as human cancers (see our collaborations with groups at Roswell Park Comprehensive Cancer Center, RPCCC).
Much of the primary work in my laboratory has been focused on understanding the molecular mechanisms behind how the viral replicative DNA helicases (polyomavirus Large T-antigen and the HPV E1 protein) interface with cellular DNA replication proteins, including but not limited to: the ssDNA binding complex, topoisomerase, and the cellular replicative DNA polymerases, recruit and use these cellular proteins to replicate their viral genomes. My laboratory has identified most of the interactions of HPV E1 with cellular DNA replication factors, identified the roles of some of these interactions in the replication process, and continue to study these interactions, both for understanding the process as well as for leveraging this knowledge for development of antivirals. During the COVID19 crisis, in collaboration with Dr. Spyridon Stavrou, we developed a cell-based system for screening for compounds/drugs that inhibit the SARS-CoV-2 Main Protease (the enzyme that Pfizer’s subsequent antiviral drug, Paxlovid, targets).
Our second primary area of investigation is elucidating how the cellular DNA damage response (DDR) pathways inhibit DNA replication when cells are subjected to DNA damage. There are many different pathways that arrest different aspects of DNA replication, including both different aspects of initiation, as well as the elongating DNA replication fork. Our recent publications in IJMS and Nucleic Acids Research show one example of this; how phosphosphorylation at a specific amino acid on a DNA helicase can slow DNA replication fork progression nearly 10-fold. One of the long-term goals of studying these DNA damage “checkpoints” is that cancer cells evolve to bypass some DNA damage checkpoints to allow the cancer cells to replicate themselves in spite of DNA breaks/genomic instability. Several years ago we developed a novel assay to assess the protein kinase activity of an apical DDR kinase, ATR, which we ultimately provided to Astra Zeneca, who currently has an ATR inhibitor in clinical trials for various cancers. Our past work and knowledge of DNA replication and the effects of DDR kinase inhibitors on cellular DNA replication has led to the studies with Dr. Joyce Ohm's and Dr. Andrei Bakin's laboratories at RPCCC on improved treatments for human cancers.
I also have ongoing collaborations with Dr. Yijun Sun on the evolution of cancer using bioinformatics and AI, with Drs. Zackary Falls and Ram Samudrala on AI-guided drug development, and with Drs. Kavi Mehta and Kinjal Majumder at the University of Wisconsin at Madison on our HPV DNA replication studies. Deeply committed to junior faculty development, many of my collaborations are with Assistant or early-stage Associate Professors.
I am a past Director of the Witebsky Center for Microbial Pathogenesis & Immunology, previously a dynamic Research Center, that in recent years has transitioned to focus on trainee development, collaboration development and hosting conferences. I have taught substantially at the undergraduate, graduate and professional (dental and medical) levels, and received the coveted UB Innovation in Teaching award. I serve on the Genetics, Genomics and Bioinformatics Steering Committee responsible for overseeing MS and PhD student progress in that graduate program, and previously served on the Steering and Admissions Committees for the Jacob's School's PhD Program in Biomedical Sciences. In our research group I typically train undergraduate, master’s and doctoral students, postdoctoral scholars, assistant research professors and laboratory technicians. Nearly all my trainees continue on to either further education, or positions in research and/or related areas such as IP law. Several of my trainees have obtained tenure-track faculty/researcher positions at research institutions/universities.