department of pharmacology

Anthony Berdis, Ph.D.

Berdis

Assistant Professor
 

Phone: (216) 368-4723
Fax: (216) 368-3395
E-mail: anthony.berdis@case.edu
W341 Wood Building

Laboratory

Research

My research program explores the dynamics of precise and pro-mutagenic DNA synthesis. DNA replication is catalyzed through the concerted action of a confederation of distinct proteins and enzyme activities. We hypothesize that the proper coordination/communication of the DNA polymerase with other proteins associated with the replication fork is essential for maintaining genomic fidelity. By inference, defects in this coordination are predicted to enhance disease development by increasing the frequency of mutagenic events. Understanding these processes at their fundamental level will provided insight into the molecular mechanism of disease development and potentially lead to therapies that prevent and/or treat carcinogenesis.

Our research is divided into two distinct yet inter-related programs. The first program studies the molecular mechanisms involved in the proper assembly and coordination of various protein components associated with the moving DNA replication fork. The second program then integrates this information into translational research to rationally design, synthesize, and test various compounds as inhibitors of DNA replication.

Replicase Function : Our studies utilize purified proteins and defined DNA substrates to evaluate if the accessory proteins allow the DNA polymerase to extend beyond various forms of DNA damage. Mutant DNA polymerases are also tested for their ability to perform translesion DNA replication. These studies are designed to identify the functional role of key amino acids in the maintenance of fidelity as well as to investigate how communication among these proteins is affected by perturbations in the activities of the DNA polymerase.

Inhibitors of DNA Replication : Using principles of rational drug design, we have developed several potent inhibitors of DNA synthesis by creating non-nucleoside molecules that are selectively inserted opposite damaged DNA. Once inserted, the molecules act as chain terminators to prevent propagation of potential genomic errors. Our in vitro studies provide a template for future studies designed to evaluate the inhibitory effects of these nucleoside analogs on cellular proliferation. This project will culminate into translational research to test these novel non-nucleoside analogs as potential chemotherapeutic and/or antiviral agents.

Selected References:

Ignatov, M., Berdis, A.J., LeGrice, S., and Barkley, M.D. Attenuation of DNA replication by HIV-1 reverse transcriptase near the central termination sequence. Biochemistry (In press)

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

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.

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.

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

Reineks, E. & 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.

Trakselis, M., Berdis, A. J., & 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.

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

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

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

BOOK CHAPTERS

Berdis, A. J. and Lee, I. (2004) Kinetic analysis of single and multiple substrate enzyme reactions. Enzymes and Their Inhibition: Drug Development. CRC Press, London, Smith and Simons, eds.

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