Drohat, Alexander - University of Maryland-Baltimore - Department of Biochemistry and Molecular Biology

个人简介

1988: B.S., Aerospace Engineering, University of Maryland College Park 1997: Ph.D., Biochemistry and Molecular Biology, University of Maryland Baltimore

研究领域

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.

近期论文

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Drohat AC, Maiti A (2014) Mechanisms for enzymatic cleavage of the N-glycosidic bond in DNA. Org Biomol Chem, Epub 2014 Aug 15. Coey CT, Fitzgerald ME, Maiti A, Reiter KH, Guzzo CM, Matunis MJ, Drohat AC (2014) E2-mediated Small Ubiquitin-like Modifier (SUMO) Modification of Thymine DNA Glycosylase Is Efficient but Not Selective for the Enzyme-Product Complex, J Biol Chem 289, 15810-15819. Maiti A, Michelson AZ, Armwood CJ, Lee JK, Drohat AC (2013) Divergent Mechanisms for Enzymatic Excision of 5-formylcytosine and 5-carboxylcytosine from DNA, J Am Chem Soc, 135, 15813-15822. Manvilla BA, Pozharski E, Toth EA, and Drohat AC (2013) Structure of human apurinic/apyrimidinic endonuclease 1 with the essential Mg2+ cofactor, Acta Cryst. D69, 2555-2562. Luncsford PJ, Manvilla BA, Patterson DN, Malik SS, Jin J, Hwang BJ, Gunther R, Kalvakolanu S, Lipinski LJ, Yuan W, Lu W, Drohat AC, Lu AL, Toth EA (2013) Coordination of MYH DNA glycosylase and APE1 endonuclease activities via physical interactions, DNA Repair, 12, 1043-1052. Illuzzi JL, Harris NA, Manvilla BA, Kim D, Li M, Drohat AC, Wilson DM 3rd (2013) Functional assessment of population and tumor-associated APE1 protein variants, PLoS One 8, e65922. Maiti A, Pozharski E, and Drohat AC (2012) How a Mismatch Repair Enzyme Balances the Needs for Efficient Lesion Processing and Minimal Action on Undamaged DNA, Cell Cycle 11, 3345-6 Maiti A, Noon, MS, Mackerell AD Jr., Pozharski E, and Drohat AC (2012) Lesion processing by a repair enzyme is severely curtailed by residues needed to prevent aberrant activity on undamaged DNA, Proc Natl Acad Sci USA, 109, 8091-6.. Manvilla BA, Maiti A, Begley MC, Toth EA, and Drohat AC (2012) Crystal Structure of Human Methyl-Binding Domain IV Glycosylase Bound to Abasic DNA, J Mol Biol, 420, 164-175. Manvilla BA, Wauchope O, Seley-Radtke KL, and Drohat AC (2011) NMR Studies Reveal an Unexpected Binding Site for a Redox Inhibitor of AP Endonuclease 1, Biochemistry, 50;10540-10549. Maiti A, Drohat AC (2011) Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: Potential implications for active demethylation of CpG sites, J Biol Chem 286, 35334-35338. Maiti A, Drohat AC (2011) Dependence of substrate binding and catalysis on pH, ionic strength, and temperature for thymine DNA glycosylase: Insights into recognition and processing of G•T mispairs. DNA Repair, 10: 545-553. Morgan MT, Maiti A, Fitzgerald ME, Drohat AC (2011) Stoichiometry and affinity for thymine DNA glycosylase binding to specific and nonspecific DNA. Nucleic Acids Res, 39:2319-29. Manvilla BA, Varney KM, Drohat AC (2010) Chemical shift assignments for human apurinic/apyrimidinic endonuclease 1.Biomol NMR Assign 4, 5-8. Maiti A, Morgan MT, Drohat AC (2009) Role of two strictly conserved residues in nucleotide flipping and N-glycosylic bond cleavage by human thymine DNA glycosylase, J Biol Chem 284, 36680-8. 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. 283, 32680-90. 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.