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

• Weirath NA, Hurben AK, Chao C, Pujari SS, Cheng T, Liu S, Tretyakova NY. Small Molecule Inhibitors of TET Dioxygenases: Bobcat339 Activity Is Mediated by Contaminating Copper(II). ACS Med Chem Lett. 2022 Apr 21;13(5):792-798. doi: 10.1021/acsmedchemlett.1c00677. PMID: 35586434; PMCID: PMC9109264.
• Rajczewski, A. T., Han, Q., Mehta, S., Kumar, P., Jagtap, P. D., Knutson, C. G., Fox, J. G., Tretyakova, N. Y., & Griffin, T. J. (2022). Quantitative Proteogenomic Characterization of Inflamed Murine Colon Tissue Using an Integrated Discovery, Verification, and Validation Proteogenomic Workflow. Proteomes, 10(2). PubMed Central ID Number: PMC9036229 doi: 10.3390/proteomes10020011
• Wang, X., Sarver, A. L., Han, Q., Seiler, C. L., Xie, C., Lu, H., Forster, C. L., Tretyakova, N. Y., & Hallstrom, T. C. (2022). UHRF2 regulates cell cycle, epigenetics and gene expression to control the timing of retinal progenitor and ganglion cell differentiation. Development (Cambridge, England), 149(6). PubMed Central ID Number: PMC8984156 doi: 10.1242/dev.195644
• Kirman, C. R., North, C. M., Tretyakova, N. Y., Erraguntla, N., Shen, H., & Hays, S. M. (2022). Use of biomarker data and metabolite relative potencies to support derivation of noncancer reference values based on the reproductive and developmental toxicity effects of 1,3-butadiene. Regulatory toxicology and pharmacology : RTP, 134, 105239. doi: 10.1016/j.yrtph.2022.105239
• Hurben AK, Tretyakova NY. Role of Protein Damage Inflicted by Dopamine Metabolites in Parkinson's Disease: Evidence, Tools, and Outlook. Chem Res Toxicol. 2022 Oct 17;35(10):1789-1804. doi: 10.1021/acs.chemrestox.2c00193. Epub 2022 Aug 22. PMID: 35994383.
• Hurben AK, Ge P, Bouchard JL, Doran TM, Tretyakova NY. Photocaged dicarbonyl probe provides spatiotemporal control over protein glycation. Chem Commun (Camb). 2022 Jan 18;58(6):855-858. doi: 10.1039/d1cc06651j. PMID: 34935009.
• Pujari SS, Jokipii Krueger CC, Chao C, Hutchins S, Hurben AK, Boysen G, Tretyakova N. DEB-FAPy-dG Adducts of 1,3-Butadiene: Synthesis, Structural Characterization, and Formation in 1,2,3,4-Diepoxybutane Treated DNA. Chemistry. 2022 Jan 13;28(3):e202103245. doi: 10.1002/chem.202103245. Epub 2021 Dec 2. PMID: 34767297.