Department of Pharmacology and Molecular Sciences
School of Medicine
B.S. 1987,University of Washington, Seattle
Ph.D. 1993, Johns Hopkins University
725 N. Wolfe Street
Baltimore, MD 21205
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.
Seamon, K.J., Sun, Z., Shlyakhtenko, L.S, Lyubchenko, Y.L., and Stivers, J.T. (2015) SAMHD1 is a Single-Stranded Nucleic Acid Binding Protein with No Active Site-Associated Nuclease Activity Nucleic Acids Res. 43, 6486-99.
Cravens, S.L., Schonhoft, J.D., Rowland, M.M., Rodriguez, A.A., Anderson, B.G., Stivers, J.T. (2015) Molecular crowding enhances facilitated diffusion of two human DNA glycosylases. Nucleic Acids Res. 43, 4087-97.
Seamon K.J., Stivers J.T. (2015) A high-throughput enzyme-coupled assay for SAMHD1 dNTPase. J Biomol Screening, 20, 801-9.
Rowland, M., J.D. Schonhoft, J.T. Stivers. (2014) Microscopic Mechanisim of DNA Damage Searching by hOGG1. Nucleic Acids Res. 42:9295-03.
Seamon, K.J., E.C. Hansen, A. Kadina, B. Kashemirov, C. McKenna, N. Bumpus, and J.T. Stivers. (2014) Small Molecule Inhibition of SAMHD1 dNTPase Through Tetramer Destabilization. J. Am. Chem. Soc. 136:9822-9825.
Hansen, E.C., K.J. Seamon, S.L. Cravens, and J.T. Stivers. (2014) GTP Activator and dNTP Substrates of HIV-1 Restriction Factor SAMHD1 Generate a Long-lived Activated State. Proc. Natl. Acad. Sci. USA. 111: E1843-1851.
Weil, A.F., D. Ghosh, Y. Zhoub, L. Seiple, M.A. McMahon, A.M. Spivak, R.F. Siliciano, and J.T. Stivers. (2013) Uracil DNA Glycosylase Initiates Degradation of HIV-1 cDNA Containing Misincorporated dUTP and Prevents Viral Integration. Proc. Natl. Acad. Sci. USA. 110:E448-457.
Nabel, C.S., H. Jia, Y. Ye, Y. Shen, H.L. Goldschmidt, J.T. Stivers, Y. Zhang, and R.M. Kohli. (2011) AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nature Chem. Biol. 8:751-758.
Schonhoft, J.D., and J.T. Stivers. (2012) Timing facilitated site transfer of an enzyme on DNA. Nature Chem. Biol. 8:205-210.
Chung, S., J.B. Parker, M. Bianchet, L.M. Amzel, and J.T. Stivers. (2009) Impact of linker strain and flexibility in the design of a fragment-based inhibitor. Nature Chem. Biol. 5:407-413.