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. We are also interested in the epigenetic effects of uracil when it is present in DNA. 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.
Cui J, Gizzi A, Stivers JT. Deoxyuridine in DNA has an inhibitory and promutagenic effect on RNA transcription by diverse RNA polymerases. Nucleic Acids Res. 2019 PMID: 30892639.
Hansen EC, Ransom M, Hesselberth JR, Hosmane NN, Capoferri AA, Bruner KM, Pollack RA, Zhang H, Drummond MB, Siliciano JM, Siliciano R, Stivers JT. Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells. Elife. 2016 PMID: 27644592.
Hansen EC, Seamon KJ, Cravens SL, Stivers JT. GTP activator and dNTP substrates of HIV-1 restriction factor SAMHD1 generate a long-lived activated state. Proc Natl Acad Sci U S A. 2014 PMID: 24753578.
Weil AF, Ghosh D, Zhou Y, Seiple L, McMahon MA, Spivak AM, Siliciano RF, Stivers JT. Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration. Proc Natl Acad Sci U S A. 2013 PMID: 23341616.
Parker JB, Bianchet MA, Krosky DJ, Friedman JI, Amzel LM, Stivers JT. Enzymatic capture of an extrahelical thymine in the search for uracil in DNA. Nature. 2007 PMID: 17704764.