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James T. Stivers, Ph.D.

Photo of Dr. James T. Stivers, Ph.D.

Professor of Pharmacology and Molecular Sciences

Research Interests: DNA repair mechanisms; small molecule inhibitors of DNA repair enzymes; dNTP pool regulation and mutagenesis

Contact for Research Inquiries

725 N. Wolfe Street
Wood Basic Science Building
Baltimore, MD 21205 map
Phone: 410-502-2758
Fax: 410-955-3023

Background

Dr. James Stivers is a professor of pharmacology and molecular sciences and oncology at the Johns Hopkins School of Medicine. His research focuses on the DNA damage recognition and the multifacted functions of uracil in DNA metabolism.

His team is currently studying the role of dUTP and dNTP pool levels in cancer therapy and innate immunity against viruses and how enzymes find rare damaged bases in DNA.

Dr. Stivers received his undergraduate degree from the University of Washington. He earned his Ph.D. from Johns Hopkins University.

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Titles

  • Professor of Pharmacology and Molecular Sciences
  • Professor of Oncology

Education

Degrees

  • Ph.D., Johns Hopkins University (Maryland) (1992)

Research & Publications

Research Summary

Dr. Stiver's laboratory is broadly interested in the biology of the RNA base uracil when it is present in DNA. Our work involves structural and biophysical studies of uracil recognition by DNA repair enzymes, the central role of uracil in adapative and innate immunity, and the function of uracil in antifolate and fluoropyrimidine chemotherapy. Accordingly, we use a wide breadth of structural, chemical, genetic and biophysical approaches that provide a fundamental understanding of molecular function. Our long-range goal is to use this understanding to design novel small molecules that alter biological pathways within a cellular environment. One approach we are developing is the high-throughput synthesis and screening of small molecule libraries directed at important targets in cancer and HIV-1 pathogenesis.

Lab

My laboratory is currently focusing on the following resaerch areas:

  • We are interested in how the simple nucleotide dUTP plays a role in the action of several antimetabolite drugs and how dUTP pool levels are used as an innate immune defense against viruses. We investigate the mechanisms for both of these uracil-centric problems using advanced biophysical and cell biology approaches. Our goal is to uncover new targets for antiviral and anticancer therapeutic development.
  • The immune system uses both adaptive (antibody) and innate mechanisms to fight viral infections such as HIV-1. A newly discovered innate immune defense to HIV-1 is the dNTP triphosphohydrolase enzyme SAMHD1. We are elucidating the enzymatic properties of this enzyme using the tools of structural biology, enzymology, synthetic chemistry, and cell biology. We ultimately seek to understand how SAMHD1 is involved in HIV-1 infectivity of immune cells.
  • Over the last decade fragment-based drug discovery has become a well-established approach for identifying lead compounds with pharmacologic activity. We have been exploring a substrate fragment-based approach for enzyme inhibitor design against several enzymes involved in uracil DNA base excision repair, which is an important pathway in viral pathogenesis, cancer chemotherapy and the development of lymphoid cancers.
  • DNA repair enzymes must locate rare damaged bases in a large sea of undamaged bases. We have developed new methods for unraveling the fundamental mechanisms that are used to search for DNA damage. Current questions being investigated are the role of DNA and enzyme electrostatics in the process of DNA translocation, how enzymes recognize damage in the context of nucleosomes, and the development of model systems for investigating the biophysics of DNA damage recognition in crowded environments such as the human nucleus.

Lab Website: Stivers laboratory
Core Facility: 500/600 NMR Facility

Selected Publications

View all on Pubmed

Hansen, E.C., Seamon, K.J., Cravens, S.L., Stivers, J.T. (2014) GTP Activator and dNTP Substrates of HIV-1 Restriction Factor SAMHD1 Generate a Long-lived Activated State, Proc Natl Acad Sci USA 111, E1843-51. PMCID: PMC4020072

Weil, A. F., Ghosh, D, Zhoub, Y., Seiple, L., McMahon, M. A., Spivak, A. M., Siliciano, R. F. and Stivers, J.T. (2013) Uracil DNA Glycosylase Initiates Degradation of HIV-1 cDNA Containing Misincorporated dUTP and Prevents Viral Integration. Proc Natl Acad Sci USA 110, E448-57. PMCID: PMC3568341

Nabel, C.S., Jia, H., Ye,Y., Shen, Y., Goldschmidt, H.L., Stivers, J.T., Zhang, Y., and Kohli, R.M. (2012) AID/APOBEC Deaminases Disfavor Modified Cytosines Implicated in DNA Demethylation Nature Chem Biol 8, 751-758. PMCID: PMC3427411

Schonhoft, J.D. and Stivers, J. T. (2012) Timing Facilitated Site Transfer of an Enzyme on DNA Nature Chem Biol, 205-210. PMCID: PMC3262087

Parker, J. B., Bianchet, M. A., Krosky, D. J., Friedman, J. I., Amzel, L. M. and Stivers, J. T. (2007) Enzymatic Capture of an Extrahelical Thymine in the Search for Uracil in DNA Nature 449, 433-438. PMCID: PMC2754044

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