Center for Gene Regulation in Health and Disease (GRHD)

Anthony Berdis

My current research program is broadly divided into two (2) scientific areas that represent innovative approaches to develop new and safer treatments against pathological conditions such as cancer, viral infections, and the development of drug resistance. My first research program focuses on creating non-natural nucleosides and their corresponding nucleotides that function as novel chemotherapeutic agents to treat cancer. In this area, my laboratory has produced ~30 unique non-natural nucleosides that inhibit cell viability and proliferation when used alone or when combined with various DNA damaging agents. The corresponding triphosphate analogs are polymerase substrates, and their use has provided unique insight into how normal and damaged DNA is replicated via "error-free" and "error-prone" processes. Our studies with these novel analogs provide fundamental knowledge toward understanding how genomic fidelity is maintained or altered as a consequence of DNA polymerase activity. We have also converted these non-natural nucleosides into spectroscopic probes that can monitor and quantify the misreplication of damaged DNA inside living cells. These novel chemical entities provide new tools to elucidate the molecular and cellular mechanisms by which damaged DNA is misreplicated. These probes are essential toward understanding how the inappropriate replication of DNA lesions contributes to diseases such as cancer. Finally, the corresponding nucleoside analogs function as therapeutic agents against a variety of different cancers including leukemia, brain cancer, and colon cancer.

My second program is developing metal-containing nucleoside analogs as chemical agents that possess imaging capabilities. These novel "biophotonic" nucleosides function as spectroscopic probes that can effectively measure nucleoside transport at the cellular level. In addition, my laboratory is testing the ability of these compounds to function as "theranostic" agents – compounds that possess both therapeutic and diagnostic activities. Ultimately, these “theranostic” agents represent a new area in personalized medicine that may lead to more effective treatments and patient responses to chemotherapy.

  • Dr. Jung-Suk Choi
    Post Doctoral Fellow
  • Anvesh Dasari
    PhD Student
  • Jennifer Williams
    PhD Student
  • Dr. Tejal Deodhar
    Post-Doctoral Fellow
    Location: 
    SR385
  • Seol "Casey" Kim
    Undergrdauate Researcher
    Location: 
    SR385

(61) Maity, A., Teets, T, Deligounul, N., Berdis, A J., and Gray, T. G. Cyclometalated  iridium (III) complexes with deoxyribose substituents. In press Chemistry - A European Journal.

(60) Golden, J., Motea, E., Zhang, X., Choi, J.S., Feng, Y., Xu, Y., Lee, I., and Berdis, A.J. (2013) Development and characterization of a non-natural nucleoside that displays anticancer activity against solid tumors. ACS Chem Biol. Sep 16. [Epub ahead
of print] PubMed PMID: 23992753.

(59) Motea, E.A., Lee, I., and Berdis, A. J. (2013) Insights into the roles of desolvation and pi-electron interactions during DNA polymerization. ChemBioChem, 14, 489-498.

(58) Devadoss, B., Lee, I. and Berdis, A. J. Spectroscopic analysis of polymerization and exonuclease proofreading by a high-fidelity DNA polymerase during translesion DNA synthesis. Biochimica et Biophysica Acta 1834, 34-45.

(57) Ahmed, M. F., Wan, Q., Jha, S, Motea, E., Berdis, A., and Dealwis, C. Evaluating the therapeutic potential of a non-natural nucleotide that inhibits human ribonucleotide reductase. Mol. Cancer Therapeutics, 11, 2077-2086.

(56) Choi, J.S. and Berdis, A.J. (2012) Nucleoside transporters: biological insights and therapeutic applications. Future Med. Chem. 4, 1461-1478.

(55) Motea, E.A., Lee, I., and Berdis, A.J. (2012) A Non-natural nucleoside with combined therapeutic and diagnostic activities against leukemia. ACS Chem. Biol. 7, 988-998.

(54) Craig, S., Gao, L., Lee, I., Gray, T., and Berdis, A.J. (2012) Gold-containing indoles as anticancer agents that potentiate the cytotoxic effects of ionizing radiation. J. Med. Chem. 55, 2437-2451.

(53) Motea, E.A., Lee, I., and Berdis, A.J. (2012) Development of a 'clickable' non-natural nucleotide to visualize the replication of non-instructional DNA lesions. Nucleic Acids Res. 40, 2357-2367.

(52) Chavarria, D., Ramos-Serrano, A., Hirao, I, and Berdis, A. J. (2011) Exploring the roles of nucleobase desolvation and shape complementarity during the misreplication of O6-methylguanine. Journal of Molecular Biology 412, 325-339.

(51) Fishovitz, J., Li, M., Frase, H., Hudak, J., Craig, S., Ho, K., Berdis, A.J., Suzuki, C.K., and Lee, I. (2011) Active-site-directed chemical tools for profiling mitochondrial Lon protease. ACS Chemical Biology 6, 781-788.

(50) Saunders, L., Devadoss, B., Raja, G.V., O'Connor, J., Su, S., Wozniak, D., Hassett, D. J., Berdis, A. J., and Sutton, M.D. (2011) Epistatic roles for Pseudomonas aeruginosa MutS and DinB in Coping with Reactive Oxygen Species-Induced DNA Damage. PloS ONE  6, e18824.

(49) Krishnamurthy, N., Ngam, C., Berdis, A., and Montano, M. M. (2011) The Exonuclease Activity of hPMC2 is required for Transcriptional Regulation of the QR Gene and Repair of Estrogen-Induced Abasic Sites. Oncogene 30, 4731-4739.

(48) Motea, E., Lee, I., and Berdis, A. J. (2011) Quantifying the contributions of desolvation and pi-electron stacking during translesion DNA synthesis. Nucleic Acids Research 39, 1623-1637.

(47) Berdis, A. J. (2010) DNA polymerases: Perfect enzymes for an imperfect world. Biochim. Biophys. Acta. 1804, 1029-1031.

(46) Zhang, X., Motea, E., and Berdis, A. J.  (2010) Replication of a non-Natural Nucleobase Provides Evidence for Asymmetric DNA Polymerization. Biochemistry 49, 3009-3023.

(45) Eng, K. and Berdis, A. J. (2010) A novel non-natural nucleoside that influences P-glycoprotein activity and mediates drug resistance. Biochemistry 49, 1640-1648.

(44) Eng, K., Scouten-Ponticelli, S.K., Sutton, M., and Berdis, A. J. (2010) Selective inhibition of DNA replicase assembly by a non-natural nucleotide: Exploiting the structural diversity of ATP-binding sites. ACS Chem. Biol. 5, 183-194.

(43) Lee, I. and Berdis, A. J.  (2010) Non-natural nucleotides as probes for the mechanism and fidelity of DNA polymerases. Biochim Biophys Acta 1804, 1064-1080.

(42) Motea, E.A. and Berdis A. J. (2010) Terminal deoxynucleotidyl transferase: The story of a misguided DNA polymerase. Biochim Biophys Acta 1804, 1151-1166.

(41) Berdis, A. J. (2009) Mechanisms of DNA polymerases. Chemical Reviews 109, 2862-2879.

(40) Sheriff, A., Motea, E, Lee, I., and Berdis, A. J. (2008) Mechanism and dynamics of translesion DNA synthesis catalyzed by the Escherichia coli Klenow fragment. Biochemistry 47, 8527-8537.

(39) Berdis, A. J. (2008) DNA polymerases as therapeutic targets. Biochemistry 47, 8253-8260.  **Distinguished as one of the ten most accessed papers of 2008 in Biochemistry

(38) Vineyard, D., Zhang, X., Donnelly, A., Lee, I., and Berdis A J. (2007) Optimization of non-natural nucleotides for selective incorporation opposite damaged DNA. Org. Biomol. Chem. 5, 3623-3630.

(37) Devadoss B, Lee I, and Berdis A J. (2007) Enhancing the "A-rule" of translesion DNA synthesis: promutagenic DNA synthesis using modified nucleoside triphosphates. Biochemistry 46, 13752-13761.

(36) Devadoss, B. and Berdis, A. J.  (2007) Non-natural nucleotide analogs as probes of DNA polymerase activity. Current Chemical Biology 1, 241-264.

(35) Berdis, A. J. and McCutcheon, D. (2007) The use of non-natural nucleotides to probe template-independent DNA synthesis. ChemBioChem. 8, 1399-1408.

(34) Devadoss, B., Lee, I., and Berdis, A. J. (2007) Is a thymine dimer replicated via a transient abasic site intermediate? A comparative study using non-natural nucleotides. Biochemistry 46, 4486-4498.

(33) Jao, S.C., English-Ospina, S.M., Berdis, A. J., Starke, D.W., Post, C.B., and Mieyal, J.J. (2006) Computational and mutational analysis of human glutaredoxin (thioltransferase): probing the molecular basis of the low pKa of cysteine 22 and its role in catalysis. Biochemistry 45, 4785-4796.

(32) Lee, I., Berdis, A.J., and Suzuki, C.K. (2006) Recent developments in the mechanistic enzymology of the ATP-dependent Lon protease from Escherichia coli: highlights from kinetic studies. Mol Biosyst. 2, 477-483.

(31) Lee, I. and Berdis, A.  (2006) Fluorescent analysis of translesion DNA synthesis by using a novel, non-natural nucleotide analogue. ChemBioChem. 7, 1990-1997.

(30) Zhang, X., Donnelly, A., Lee, I., and Berdis, A. J. (2006) Rational attempts to optimize non-natural nucleotides for selective incorporation opposite an abasic site. Biochemistry 45, 13293-13303.

(29) Zhuang, Z., Berdis, A. J., and Benkovic, S. J. (2006) An alternative clamp loading pathway via T4 clamp loader gp44/62-DNA complex. Biochemistry 45, 7976-7989.

(28) Zhang, X., Zhou, X, Lee, I., and Berdis, A.J. (2005) Hydrophobicity, shape, and pi-electron density during translesion DNA synthesis. Journal of American Chemical Society, 128, 143-149.

(27) Zhang, X., Lee, I., and Berdis, A. J. (2005) The use of nonnatural nucleotides to probe the contributions of shape complementarity and pi-electron surface area during DNA polymerization. Biochemistry 44, 13101-13110.

(26) Zhang, X., Lee, I., and Berdis, A. J. (2005) A potential chemotherapeutic strategy for the selective inhibition of promutagenic DNA synthesis by nonnatural nucleotides. Biochemistry 44, 13111-13121.

(25) Ignatov, M., Berdis, A.J., and Barkley, M.D. (2005) Attenuation of DNA replication by HIV-1 reverse transcriptase near the central termination sequence. Biochemistry 44, 5346-5356.

(24) Patterson-Ward, J., Vineyard, D., Berdis, A. J., and Lee, I. (2005) Correlating the timing of ATP hydrolysis with proteolysis in Escherichia coli Lon protease. Biochemistry 44, 1671-1682.

(23) Zhuang, Z., Spiering, M. M., Berdis, A. J., Trakselis, M. A., and Benkovic, S. J. (2004) 'Screw-cap' clamp loader proteins that thread. Nature Structural and Molecular Biology 11, 580-581.

(22) Zhang, X., Lee, I., and Berdis, A. J. (2004) Evaluating the contributions of desolvation and base-stacking during translesion DNA replication. Org. Biomol. Chem. 2, 1703-1711.

(21) Reineks, E. Z. and Berdis, A. J. (2004) Evaluating the contribution of base stacking during translesion DNA replication. Biochemistry 43, 393-404.   

(20) Reineks, E. and Berdis, A. J. (2003) Evaluating the effects of enhanced processivity and metal ions on translesion DNA replication catalyzed by the bacteriophage T4 DNA polymerase. Journal of Molecular Biology 326, 435-451.

(19) Trakselis, M., Berdis, A. J., and Benkovic, S. J. (2003) Examination of the role of the clamp-loader and ATP hydrolysis in the formation of the bacteriophage T4 polymerase holoenzyme. Journal of Molecular Biology 326, 435-451.

(18) Hays, H. and Berdis, A. J. (2002) Manganese substantially alters the dynamics of translesion DNA synthesis. Biochemistry 41, 4771-4778.

(17) Berdis, A. J., Stetor, S. R., LeGrice, S. F., and Barkley, M. D. (2001) Molecular mechanism of sequence specific termination of lentiviral replication. Biochemistry 40, 12140-12149.

(16) Berdis, A. J. (2001) Dynamics of translesion DNA synthesis catalyzed by the bacteriophage T4 exonuclease-deficient DNA polymerase. Biochemistry 40, 7180-7191.

(15) Lee, I. and Berdis, A.J. (2001) Adenosine triphosphate-dependent degradation of a fluorescent lambda N substrate mimic by Lon protease. Anal. Biochem. 291, 74-83.

Publications during Graduate and Post-Doctoral Studies

(14) Berdis, A.J. and Benkovic, S.J. (1998) Simultaneous formation of functional leading and lagging strand holoenzyme complexes on a small, defined DNA substrate. Proc. Natl. Acad. Sci. USA. 95, 11128-11133.

(13) Hwang, C.C., Berdis, A.J., Karsten, W.E., Cleland, W.W., and Cook, P.F. (1998) Oxidative decarboxylation of 6-phosphogluconate by 6-phosphogluconate dehydrogenase proceeds by a stepwise mechanism with NADP and APADP as oxidants. Biochemistry 37, 12596-12602.

(12) Sexton, D.J., Berdis, A.J., and Benkovic, S.J. (1997) Assembly and disassembly of DNA polymerase holoenzyme. Curr. Opin. Chem. Biol. 1, 316-322.

(11) Sexton, D.J., Kaboord, B.F., Berdis, A.J., Carver, T.E., and Benkovic, S.J. (1998) Dissecting the order of bacteriophage T4 DNA polymerase holoenzyme assembly. Biochemistry 37, 7749-7756.

(10) Berdis, A.J., Lee, I., Coward, J.K., Stephens, C., Wright, R., Shapiro, L., and Benkovic, S.J. (1998) A cell cycle-regulated adenine DNA methyltransferase from Caulobacter crescentus processively methylates GANTC sites on hemimethylated DNA. Proc. Natl. Acad. Sci. USA 95, 2874-2879.

(9) Berdis, A.J. and Benkovic, S.J. (1997) Mechanism of bacteriophage T4 DNA holoenzyme assembly: the 44/62 protein acts as a molecular motor. Biochemistry 36, 2733-2743.

(8) Berdis, A.J., Soumillion, P., and Benkovic, S.J. (1996) The carboxyl terminus of the bacteriophage T4 DNA polymerase is required for holoenzyme complex formation. Proc. Natl. Acad. Sci. USA 93, 12822-7.

(7) Sexton, D.J., Carver, T.E., Berdis, A.J., and Benkovic, S.J. (1996) Protein-protein and protein-DNA interactions at the bacteriophage T4 DNA replication fork. Characterization of a fluorescently labeled DNA polymerase sliding clamp. J. Biol. Chem. 271, 28045-28051.

(6) Berdis, A.J. and Benkovic, S.J. (1996) Role of adenosine 5'-triphosphate hydrolysis in the assembly of the bacteriophage T4 DNA replication holoenzyme complex. Biochemistry 35, 9253-9265.

(5) Yoon, M.Y., Thayer-Cook, K.A., Berdis, A.J., Karsten, W.E., Schnackerz, K.D., and Cook, P.F. (1995) Acid-base chemical mechanism of aspartase from Hafnia alvei. Arch. Biochem. Biophys. 320, 115-122.

(4) Stewart, J.D., Krebs, J.F., Siuzdak, G., Berdis, A.J., Smithrud, D.B., and Benkovic SJ. (1994) Dissection of an antibody-catalyzed reaction. Proc. Natl. Acad. Sci. USA 91, 7404-7409.

(3) Berdis, A.J. and Cook, P.F. (1993) The 2'-phosphate of NADP is critical for optimum productive binding to 6-phosphogluconate dehydrogenase from Candida utilis. Arch. Biochem. Biophys. 305, 551-558.

(2) Berdis, A.J. and Cook, P.F. (1993) Chemical mechanism of 6-phosphogluconate dehydrogenase from Candida utilis from pH studies. Biochemistry 32, 2041-2046.

(1) Berdis, A.J. and Cook, P.F. (1993) Overall kinetic mechanism of 6-phosphogluconate dehydrogenase from Candida utilis. Biochemistry 32, 2036-2040.

BOOK CHAPTERS

(3) Berdis, AJ. (2011) "Chemotherapeutic Intervention by Inhibiting DNA Polymerases." DNA Repair in Cancer Therapy: Molecular Targets and Clinical Applications. Elsevier Publishing, Edited by Mark Kelley.

(2) Berdis, A. J. and Lee, I. (2004) "Kinetic analysis of single and multiple substrate enzyme reactions." Enzyme Mechanisms for Undergraduate Research. Taylor Publishing.

(1) Berdis, A. J. (2003) "Analysis of translesion DNA replication using transient kinetic methodologies." Recent Research Developments in Analytical Biochemistry. Transworld Research Network.