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Alexander Drohat
Ph.D.
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| Academic Title:
Assistant Professor |
| Primary Appointment:
Biochemistry and Molecular Biology |
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adroh001@umaryland.edu |
| Location:
108 N. Greene St.,
419 |
| Phone:
(410) 706-8118 |
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Personal History
EDUCATION
- 1988 B.S., Aerospace Engineering, University of Maryland College Park
- 1997 Ph.D., Biochemistry and Molecular Biology, University of Maryland Baltimore
POST GRADUATE EXPERIENCE
- 1998-2000 National Research Council Postdoctoral Fellow, Center for Advanced Research in Biotechnology (CARB) of the University of Maryland Biotechnology Institute and the National Institute of Standards and technology
- 2001-2002 Postdoctoral Fellow, Johns Hopkins University School of Medicine
Research Interests
We use NMR spectroscopy and a variety of other biophysical, biochemical, and molecular biological approaches to determine the structure and elucidate mechanism of DNA repair enzymes. The reactive nucleobases of DNA are continuously damaged (chemically modified) by cellular metabolites and exogenous agents, producing cytotoxic and/or mutagenic lesions that play a role in the development of disease and in ageing. Counteracting this inevitable threat is the base excision repair (BER) pathway, initiated by a damage-specific DNA glycosylase. Using a base-flipping mechanism, these enzymes find and remove damaged and mismatched bases in the vast expanse of normal DNA. While some DNA glycosylases exhibit significant catalytic power, they are perhaps more impressive for their extraordinary specificity for certain lesions and against normal bases. Some DNA glycosylases recognize a single lesion, whereas others are more permissive and can remove multiple forms of damage. We are studying two human DNA glycosylases that are specific for G/T and G/U mispairs in addition to numerous other lesions. A central question we are addressing is how these enzymes achieve specificity for a broad range of lesions while avoiding normal bases. We are also investigating the general question of how the activity of DNA glycosylases is stimulated by AP endonuclease, the follow-on enzyme in BER, i.e. how are the first two steps of BER coupled? Finally, we are interested in characterizing and understanding the biological role of protein-protein interactions among BER enzymes, and involving BER enzymes and proteins from other pathways.
Publications
Fitzgerald M.E. and Drohat A.C. (2008) Coordinating the Initial Steps of Base Excision Repair: AP Endonuclease 1 Actively Stimulates Thymine DNA Glycosylase by Disrupting the Product Complex, J. Biol. Chem., published online 9-19-2008.
Fitzgerald, M.E, and Drohat, A.C. (2008) Structural Studies of RNA/DNA Polypurine Tracts. Chem. Biol. 15: 203-204. (Invited Commentary).
Maiti, A., Morgan, M.T., Pozharski, E., and Drohat A.C. (2008) Crystal Structure of Human Thymine DNA Glycosylase Bound to DNA Elucidates Sequence-Specific Mismatch Recognition, Proc. Natl. Acad. Sci. U.S.A. 105, 8890-8895.
Michael T. Morgan, Matthew T. Bennett, and Alexander C. Drohat, Excision of 5-Halogenated Uracils by Human Thymine DNA Glycosylase: Robust Activity for DNA Contexts Other than CpG. J. Biol. Chem. 2007 282: 27578- 27586.
Bennett, M.T., Rodgers, M.T., Hebert, A.S., Ruslander, L.E., Eisele, L., and Drohat, A.C. (2006) Specificity of Human Thymine DNA Glycosylase Depends on N-Glycosidic Bond Stability, J. Am. Chem. Soc. 128, 12510-12519.
Cao, C., Kwon, K., Jiang, Y.L., Drohat, A.C., and Stivers, J.T. (2003) Solution structure and base perturbation studies reveal a novel mode of alkylated base recognition by 3-methyladenine DNA glycosylase I, J. Biol. Chem. 278: 48012-48020.
Jiang, Y.L., Drohat, A.C., Ichikawa, Y., and Stivers, J.T. (2002) Probing the Limits of Electrostatic Catalysis by Uracil DNA Glycosylase Using Transition-State Mimicry and Mutagenesis, J. Biol. Chem. 277: 15385-15392.
Drohat, A.C., Kwon, K., Krosky, D.L., and Stivers, J.T. (2002) 3‑methyladenine DNA Glycosylase I is an Unexpected Helix-Hairpin-Helix Superfamily Member Nature Struct. Biol. 9: 659-664.
Drohat, A.C., and Stivers, J.T. (2000) NMR Evidence for an Unusually Low N1 pKa for Uracil Bound to Uracil DNA Glycosylase: Implications for Catalysis, J. Am. Chem. Soc. 122: 1840-1841.
Drohat, A.C., and Stivers, J.T. (2000) Escherichia coli Uracil DNAGlycosylase: NMR Characterization of the Short Hydrogen Bond from His187 to Uracil O2, Biochemistry 39: 11865-11875.
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