Browsing by Author "Park, Shin"

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    Chemical Synthesis of a DNA Strand Modified by a DEB-FAPy-dG Adduct of 1,3-Butadiene
    (2024-04) Den Hartog, Holly I; Kumar, Honnaiah Vijay; Park, Shin; Legaspi, Josh; Gutierréz, Simón; Lorentz, Christine; Tretyakova, Natalia Y.
    1,3-Butadiene (BD) is a known mammalian carcinogen and is found abundantly in cigarette smoke, automobile exhaust, and polymer industry settings. Upon entering the human body, BD is metabolized by cytochrome P450 monooxygenases CYP2E1 and CYP2A6 to multiple reactive electrophiles, including 1,2:3,4-diepoxybutane (DEB). DEB has the potential to alkylate the N7 position of guanine to form a formamidopyrimidine (FAPy) adduct, termed DEB-FAPy-dG. This adduct has been implicated in disease pathways and is known to be a player in carcinogenesis, but the specific mechanisms by which it acts are largely unknown. In this work, a novel synthetic pathway to chemically synthesize a phosphoramidite containing the DEB-FAPy-dG adduct is reported, which will allow for selective incorporation of the adduct into synthetic DNA. Analysis of this synthetic DNA strand will reveal how the noncanonical nucleobase may impact chain extension, base pairing, and polymerase activity, which will contribute important knowledge to the understanding of how BD and its metabolites contribute to disease. The new synthetic pathway sets the foundation for future work in this field, including the creation and analysis of a DNA strand modified by DEB-FAPy-dG and the syntheses of DNA adducts formed by other metabolites of BD, both of which will contribute to the understanding of the effects of DNA adducts and how the effects of these adducts may be mitigated.