Research Program: Carcinogenesis & Chemoprevention
Associate Professor, Department of Medicinal Chemistry

trety001@umn.edu
612-626-3432 — office
612-624-0638 — lab
Preferred method of contact: e-mail

• B.Sc., Moscow State University, Russia, 1988
• M.S., Moscow State University, Russia, 1990
• Ph.D., University of North Carolina at Chapel Hill, 1997
• Postdoctoral, Massachusetts Institute of Technology, 1999

Research Interests

Humans are exposed to complex mixtures of environmental and dietary carcinogens, as well as endogenous electrophiles produced from normal metabolism. Some of these chemicals and their metabolites are electrophilic species capable of chemical reactions with DNA. The resulting covalently modified DNA nucleobases (DNA adducts) have distorted base pairing characteristics and, if not repaired, can be converted to heritable mutations during DNA replication. Carcinogen-induced changes in critical genes that control cell growth and differentiation can lead to the initiation of cancer. Paradoxically, many common antitumor drugs use a similar mechanism by alkylating DNA in an attempt to induce tumor cell death. Long-term cancer survivors are at risk for secondary cancers resulting from exposure to antineoplastic agents. The focus of our research is to investigate the structural basis for promutagenic and anticancer activity of DNA-modifying agents. The primary experimental tool employed in our laboratory is biological mass spectrometry (ESI-MS, cap HPLC-MS, MS/MS, and MALDI-TOF MS), although most of the projects also involve organic synthesis, structural analyses (e.g. NMR, 2D NMR, CD spectroscopy), and molecular modeling of chemically altered DNA.

For a more detailed description of Dr. Tretyakova's research interests, please visit her Department of Medicinal Chemistry Web site.

Selected Publications

Balcome S, Park S, Quirk-Dorr DR, Hafner L, Phillips L, Tretyakova N.Adenine-containing DNA-DNA cross-links of antitumor nitrogen mustards. Chem Res Toxicol, 2004;17:950-962.

Thomson NM, Mijal RS, Ziegel R, Fleischer NL, Pegg AE, Tretyakova NY, Peterson LA. Development of a quantitative liquid chromatography/electrospray mass spectrometric assay for a mutagenic tobacco specific nitrosamine-derived DNA adduct, O6-[4-oxo-4-(3-pyridyl)butyl]-2'-deoxyguanosine. Chem Res Toxicol, 2004;17:1600-1606.

Ziegel R, Shallop A, Upadhyaya P, Jones R, Tretyakova N. Endogenous 5-methylcytosine protects neighboring guanines from N7 and O6-methylation and O6-pyridyloxobutylation by the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Biochemistry 2004;43:540-549.

Park S, Hodge J, Anderson C, Tretyakova N.Guanine-adenine DNA cross-linking by 1,2,3,4-diepoxybutane: potential basis for biological activity. Chem Res Toxicol, 2004;17:1638-1651.

Rajesh M, Wang G, Jones R, Tretyakova N. Stable sotope abeling-mass spectrometry analysis of methyl- and pyridyloxobutyl-guanine adducts of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in p53-derived DNA sequences. Biochemistry 2005;44:2197-2207.

Park S, Anderson C,Wang G, Jones R,Tretyakova N. Interstrand and intrastrand DNA-DNA cross-linking by 1,2,3,4-diepoxybutane: role of stereochemistry. J Am Chem Soc. 2005;127:14355-14365.

Kim J, Park S, Tretyakova NY, Wagner CR. A method for quantitating the intracellular metabolism of AZT amino acid phosphoramidate pronucleotides by capillary high-performance liquid chromatography-electrospray ionization mass spectrometry. Mol Pharm. 2005;2:233-41.

Millard, J.T., Hanly, T.C., Murphy, K., and Tretyakova, N. (2006) The 5'-GNC Site for DNA Interstrand Cross-Linking is Conserved for Diepoxybutane Stereoisomers. Chem. Res. Toxicol., 19, 16-19.

Malejka-Giganti M, Tretyakova N. Molecular mechanisms of carcinogenesis. In Carcinogenic and anticarcinogenic food components. (Baer-Dubowska, W., Bartoszek, A., and Malejka-Giganti, D. Eds.), 2006; CRC Press, Boca Raton, FL, pp 13-36.

Loeber R, Rajesh M, Pegg A, Tretyakova N. Cross-linking of the human DNA repair protein O6-alkylguanine DNA alkyltransferase to its DNA substrate in the presence of 1,2,3,4-diepoxybutane. Chem Res Toxicol. 2006;19:645-54.

Guza R, Rajesh M, Fang Q, Pegg AE, Tretyakova N. Kinetics of O(6)-methyl-2'-deoxyguanosine repair by O(6)-alkylguanine DNA alkyltransferase within K-ras gene-derived DNA sequences. Chem Res Toxicol. 2006;19:531-538.

Matter B, Malejka-Giganti D, Csallany AS, Tretyakova N.Quantitative analysis of the oxidative DNA lesion, 2,2-diamino-4-(2-deoxy-ß-D-erythro-pentofuranosyl)amino]-5(2H)-oxazolone (oxazolone), in vitro and in vivo by isotope dilution-capillary HPLC-ESI-MS/MS. Nuc Acids Res. 2006;34:5449-5460.

Tretyakova N, Livshits A, Park S, Bisht B, Goggin M. Structural elucidation of a novel DNA-DNA cross-link of 1,2,3,4-diepoxybutane. Chem Res Toxicol. 2007;20:284-289.

Dorr D, Murphy K, Tretyakova N. Synthesis of DNA oligodeoxynucleotides containing structurally defined N6-(2'-hydroxy-3',4'-buten-1'-yl)-adenine adducts of 3,4-epoxy-1-butene. Chem Biol Interact. 2007;166:104-111.

Antsypovich S, Quirk Dorr D, Pitts C, Tretyakova N. Site specific N6-(2-hydroxy-3,4-epoxybut-1-yl)adenine oligodeoxynucleotide adducts of 1,2,3,4 diepoxybutane: synthesis and stability at physiological pH. Chem Res Toxicol. 2007;20:641-649.

Kim MY, Park S, Tretyakova N, Wogan G. Mutagenesis of the supF gene by stereoisomers of 1,2,3,4-diepoxybutane. Chem Res Toxicol. 2007;20:790-797.

Goggin M, Loeber R, Park S, Walker V, Wickliffe J, Tretyakova. N. HPLC-ESI+-MS/MS analysis of N7-guanine-N7-guanine DNA cross-links in tissues of mice exposed to 1,3-butadiene. Chem Res Toxicol. 2007;20:839-847.

Matter B, Guza R, Zhao J, Li Z, Jones R, Tretyakova N. Sequence distribution of acetaldehyde-derived N2-ethyl-dG adducts along duplex DNA. Chem Res Toxicol. 2007;20:1379-1387.

Miksa B, Chinnapann R, Dang NC, Reppert M, Matter B, Tretyakova N, Grubor N, Jankowiak R. Spectral differentiation and immunoaffinity capillary electrophoresis separation of enantiomeric benzo(a)pyrene diol epoxide-derived DNA adducts. Chem Res Toxicol. 2007;20:192-1199.

Loeber R, Michaelson E, Fang Q, Campbell C, Pegg AE, Tretyakova N. Cross-linking of the DNA repair protein O6-alkylguanine DNA alkyltransferase to DNA in the presence of antitumor nitrogen mustards. Chem Res Toxicol. 2008 [Epub ahead of print].