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Dr. James Stivers

Ph.D.
Titles

Associate Professor of Pharmacology and Molecular Sciences
Associate Professor of Oncology

Research Summary

Over the last five years, a unique program has begun that seeks to obtain a fundamental understanding of the chemical mechanisms by which enzymes repair damaged DNA and to use this information to design small-molecule inhibitors of these enzymes. The driving force for these efforts is the recognition that the effectiveness of cancer chemotherapy regimens is intimately connected to, and in some cases directly relies on, DNA damage repair pathways. Such mechanisms are poorly characterized, and a more sophisticated understanding of the roles of DNA damage repair in the pharmacology of DNA damaging agents could provide new treatment approaches. It is hypothesized that inhibitors of DNA repair enzymes will dramatically increase the effectiveness of existing chemotherapy regimens by introducing increased amounts of DNA damage. Such levels of damage could lead to cell death by apoptosis, or alternatively, by nonapoptotic mechanisms, thereby bypassing the dependence on the apoptotic machinery that is frequently malfunctioning in tumor cells. An increased effectiveness of therapeutic agents may allow the clinician to achieve positive outcomes at lower drug doses, thereby diminishing toxic side effects. Most significantly, the proposed line of study helps illuminate the basic question of why chemotherapy drugs fail, and more importantly, why they work at all.

Journal Citations

Bond, A.; Reichert, Z.; Stivers, J.T. Novel and specific inhibitors of a poxvirus type I topoisomerase. Molecular pharmacology. 2006 Feb;69(2):547-557.

Cao, C.; Jiang, Y.L.; Krosky, D.J.; Stivers, J.T. The catalytic power of uracil DNA glycosylase in the opening of thymine base pairs. J Am Chem Soc. 2006 Oct 11;128(40):13034-13035.

Jiang, Y.L.; Chung, S.; Krosky, D.J.; Stivers, J.T. Synthesis and high-throughput evaluation of triskelion uracil libraries for inhibition of human dUTPase and UNG2. Bioorganic & medicinal chemistry. 2006 Aug 15;14(16):5666-5672.

Seiple, L.; Jaruga, P.; Dizdaroglu, M.; Stivers, J.T. Linking uracil base excision repair and 5-fluorouracil toxicity in yeast. Nucleic Acids Res. 2006;34(1):140-151.

Nagarajan, R.; Stivers, J.T. Unmasking Anticooperative DNA-binding interactions of vaccinia DNA topoisomerase I. Biochemistry. 2007 Jan 9;46(1):192-199.

Parker, J.B.; Bianchet, M.A.; Krosky, D.J.; Friedman, J.I.; Amzel, L.M.; Stivers, J.T. Enzymatic capture of an extrahelical thymine in the search for uracil in DNA. Nature. 2007 Sep 27;449(7161):433-437.

Kim, H.; Cardellina, J.H., 2nd; Akee, R.; Champoux, J.J.; Stivers, J.T. Arylstibonic acids: novel inhibitors and activators of human topoisomerase IB. Bioorganic chemistry. 2008 Aug;36(4):190-197.

McMahon, M.A.; Siliciano, J.D.; Lai, J.; Liu, J.O.; Stivers, J.T.; Siliciano, R.F.; Kohli, R.M. The antiherpetic drug acyclovir inhibits HIV replication and selects the V75I reverse transcriptase multidrug resistance mutation. J Biol Chem. 2008 Nov 14;283(46):31289-31293.

Parker, J.B.; Stivers, J.T. Uracil DNA glycosylase: revisiting substrate-assisted catalysis by DNA phosphate anions. Biochemistry. 2008 Aug 19;47(33):8614-8622.

Porecha, R.H.; Stivers, J.T. Uracil DNA glycosylase uses DNA hopping and short-range sliding to trap extrahelical uracils. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10791-10796.

Seiple, L.A.; Cardellina, J.H., 2nd; Akee, R.; Stivers, J.T. Potent inhibition of human apurinic/apyrimidinic endonuclease 1 by arylstibonic acids. Molecular pharmacology. 2008 Mar;73(3):669-677.

Stivers, J.T. Extrahelical damaged base recognition by DNA glycosylase enzymes. Chemistry (Weinheim an der Bergstrasse, Germany). 2008;14(3):786-793.

Stivers, J.T. Small molecule versus DNA repair nanomachine. Nat Chem Biol. 2008 Feb;4(2):86-88.

Chung, S.; Parker, J.B.; Bianchet, M.; Amzel, L.M.; Stivers, J.T. Impact of linker strain and flexibility in the design of a fragment-based inhibitor. Nat Chem Biol. 2009 Jun;5(6):407-413.

Friedman, J.I.; Majumdar, A.; Stivers, J.T. Nontarget DNA binding shapes the dynamic landscape for enzymatic recognition of DNA damage. Nucleic Acids Res. 2009 Jun;37(11):3493-3500.

Huang, H.; Stivers, J.T.; Greenberg, M.M. Competitive inhibition of uracil DNA glycosylase by a modified nucleotide whose triphosphate is a substrate for DNA polymerase. J Am Chem Soc. 2009 Feb 4;131(4):1344-1345.

Kohli, R.M.; Abrams, S.R.; Gajula, K.S.; Maul, R.W.; Gearhart, P.J.; Stivers, J.T. A portable hot spot recognition loop transfers sequence preferences from APOBEC family members to activation-induced cytidine deaminase. J Biol Chem. 2009 Aug 21;284(34):22898-22904.

Friedman, J.I.; McMahon, M.T.; Stivers, J.T.; Van Zijl, P.C. Indirect detection of labile solute proton spectra via the water signal using frequency-labeled exchange (FLEX) transfer. J Am Chem Soc. 2010 Feb 17;132(6):1813-1815.

Friedman, J.I.; Stivers, J.T. Detection of damaged DNA bases by DNA glycosylase enzymes. Biochemistry. 2010 Jun 22;49(24):4957-4967.

Kohli, R.M.; Maul, R.W.; Guminski, A.F.; McClure, R.L.; Gajula, K.S.; Saribasak, H.; McMahon, M.A.; Siliciano, R.F.; Gearhart, P.J.; Stivers, J.T. Local sequence targeting in the AID/APOBEC family differentially impacts retroviral restriction and antibody diversification. J Biol Chem. 2010 Dec 24;285(52):40956-40964.

Stahley, M.R.; Stivers, J.T. Mechanism and specificity of DNA strand exchange catalyzed by vaccinia DNA topoisomerase type I. Biochemistry. 2010 Apr 6;49(13):2786-2795.

Ye, Y.; Stivers, J.T. Fluorescence-based high-throughput assay for human DNA (cytosine-5)-methyltransferase 1. Anal Biochem. 2010 Jun 1;401(1):168-172.

Friedman, J.I.; Jiang, Y.L.; Miller, P.S.; Stivers, J.T. Unique dynamic properties of DNA duplexes containing interstrand cross-links. Biochemistry. 2011 Feb 8;50(5):882-890.

Grogan, B.C.; Parker, J.B.; Guminski, A.F.; Stivers, J.T. Effect of the Thymidylate Synthase Inhibitors on dUTP and TTP Pool Levels and the Activities of DNA Repair Glycosylases on Uracil and 5-Fluorouracil in DNA. Biochemistry. 2011 Feb 8;50(5):618-627.

Parker, J.B.; Stivers, J.T. Dynamics of uracil and 5-Fluorouracil in DNA. Biochemistry. 2011 Feb 8;50(5):612-617.

 

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