Natalia Tretyakova
Distinguished McKnight University Professor
Department of Medicinal Chemistry
College of Pharmacy
Dr. Tretyakova’s laboratory is employing –omics methodologies to characterize the epigenetic effects of inflammation and cigarette smoking in the lung. She also uses cutting-edge mass spectrometry methods to characterize DNA nucleobases that are found in DNA as epigenetic marks and those that have become structurally altered by chemical reactions with carcinogens (DNA adducts). Dr. Tretyakova uses the tools of mass spectrometry and genomics to detect epigenetic changes in DNA methylation, hydroxymethylation, formylation, and carboxylation upon treatment with carcinogens and drugs. She has developed sensitive mass spectrometry based methodology for all five known epigenetic modifications of cytosine (MeC, hmC, fC, and caC) and employed RRBS/oxyRRBS methodologies to map epigenetic changes across the genome, RNA-seq to study the changes in gene expression, and mass spectrometry based proteomics to examine global changes of the proteome in response to exposure and to characterize protein modifications. She has also employed mass spectrometry-based tools to elucidate the fidelity of DNA methylating enzymes and identify protein readers of epigenetic marks of DNA and identified small molecule inhibitors of DNA demethylating enzymes. Dr. Tretyakova is an expert in mass spectrometry based proteomics and chemical epigenetics.
Research Interests
Chemical Biology
Nucleic Acids
Chemical Carcinogenesis
Nucleoside Synthesis
Mass Spectrometry
Proteomics
Identification of DNA adducts produced by Bis-electrophiles: This research aims to identify the structures of novel DNA lesions generated by bifunctional electrophiles used in chemotherapy and generated from the metabolism of xenobiotics.
Solid Phase Synthesis of DNA Oligonucleotides Containing Site- and Stereospecific DNA Adducts: Synthetic methodologies are developed to generate DNA strands containing site- and stereospecific nucleobase lesions for structural and biological studies (e.g. NMR, mutagenesis, and polymerase bypass).
Inter-individual Differences in Metabolism of Tobacco Carcinogens: Mass-spectrometry-based methodologies are employed to uncover inter-individual and ethnic differences in the metabolism of tobacco carcinogens.
DNA Sequence Effects on Reactivity: Isotope labeling approaches are used to map the reactivity of carcinogens and drugs towards DNA nucleobases as a function of local sequence context. Unnatural DNA bases are used to establish the mechanisms of sequence-dependent reactivity.
Novel Mass Spectrometry Methodologies for Quantitative Analyses of DNA damage: we are developing novel mass spectrometry methodologies for quantitative analyzes of DNA adducts in vivo (e.g. in laboratory animals and cancer patients undergoing treatment).
Proteomics Studies of DNA-protein Cross-linking: we are employing mass-spectrometry-based proteomics to characterize the protein targets of bis-electrophiles that cross-link proteins to DNA.
2002 –2013 "Sequence distribution of tobacco carcinogen-DNA adducts" (NCI 5R01 CA-095039) Research Project Grant from the NIH.
2003 –2013 "DNA cross-linking by diepoxybutane" (NIH NCI 2R01-CA100670) Research Project Grant from the NIH.
2010-2014 "Mechanisms of ethnic/racial differences in lung cancer due to cigarette smoking"(1 P01 CA138338-01A1) Program Project Grant from the NIH.
Publications
1.Seiler, C. L.; Song, J. M.; Fernandez, J.; Abrahante, J. E.; Kono, T. J. Y.; Chen, Y.; Ren, Y.; Kassie, F.; Tretyakova, N. Y. Epigenetic changes in alveolar type ii lung cells of A/J Mice following intranasal treatment with lipopolysaccharide. Chem. Res. Toxicol. 2019.
2.Lewis, L.; Chappell, G. A.; Kobets, T.; O'Brian, B. E.; Sangaraju, D.; Kosyk, O.; Bodnar, W.; Tretyakova, N. Y.; Pogribny, I. P.; Rusyn, I. Sex-specific differences in genotoxic and epigenetic effects of 1,3-butadiene among mouse tissues. Arch. Toxicol. 2019, 93, 791-800.
3.Yang, K.; Park, D.; Tretyakova, N. Y.; Greenberg, M. M. Histone tails decrease N7-methyl-2'-deoxyguanosine depurination and yield DNA-protein cross-links in nucleosome core particles and cells. Proc. Natl. Acad. Sci. U. S. A. 2018, 115, E11212-E11220.
4.Degner, A.; Carlsson, H.; Karlsson, I.; Eriksson, J.; Pujari, S. S.; Tretyakova, N. Y.; Tornqvist, M. Discovery of novel N-(4-hydroxybenzyl)valine hemoglobin adducts in human blood. Chem. Res. Toxicol. 2018, 31, 1305-1314.
5.Seiler, C. L.; Fernandez, J.; Koerperich, Z.; Andersen, M. P.; Kotandeniya, D.; Nguyen, M. E.; Sham, Y. Y.; Tretyakova, N. Y. Maintenance DNA methyltransferase activity in the presence of oxidized forms of 5-methylcytosine: structural basis for ten eleven translocation-mediated DNA demethylation. Biochemistry 2018, 57, 6061-6069.