Natalia Tretyakova, PhD

Bio

The focus of our research is to investigate the structural basis for carcinogenic and anticancer activity of DNA- and protein-modifying agents. Synthetic methodologies are developed to prepare structurally modified nucleosides and amino acids representing carcinogen- and drug-induced DNA and protein adducts. The effects of nucleobase modifications on DNA structure and stability are determined by NMR spectroscopy, mass spectrometry, CD spectroscopy, and computer modeling of chemically altered DNA. Biological mass spectrometry techniques are employed to quantify the formation of DNA and protein adducts in vivo. These studies identify the molecular targets of exogenous and endogenous electrophiles and provide an insight into the origins of their biological activity. The following projects are currently underway:

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 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 ethic differences in 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.

Research Interests

• Chemical Biology
• Nucleic Acids
• Chemical Carcinogenesis
• Nucleoside Synthesis
• Mass Spectrometry
• Proteomics

PubMed

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.