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.
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,
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.