My laboratory is broadly interested in how dNTP pool levels and composition influence genetic stability, adaptive and innate immunity, inflammation, carcinogenesis, cellular senescence and aging. Current work in the lab focuses on two key aspects of dNTP metabolism. We are elucidating how the uniquely high concentration of dUTP in resting immune cells is used as a potent HIV-1 restriction factor. In macrophages, the high dUTP levels leads to incorporation of uracil into the viral DNA during reverse transcription to form U/A base pairs. Uracil is viewed as DNA damage by the host cell, and when the uracilated viral DNA enters the nucleus, the uracils are excised by the nuclear uracil base excision repair machinery leading to viral DNA fragmentation. We are also interested in the epigenetic effects of uracil when it is present in DNA. In a second related project we are exploring how the key cellular dNTPase, SAMHD1, is regulated and the role of this enzyme in inflammation, cell senescence, cancer, and HIV-1 infection. Our long-range goal is to design novel small molecules that predictably alter the make up of nucleotide pools in cells for antiviral, anticancer, and anti-inflammatory therapeutic uses. Accordingly, we employ both fragment based design and high-throughput screening methods to discover useful small molecules.