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Shin H Cho dissertation.pdf (4.86 MB)

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DNA Adducts from 5'-Aldehyde Lesions and their Contributions to the Endogenous Exposome

Cho, Shin Hae
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1556887150041774

Abstract Details

, Doctor of Philosophy, University of Toledo, Medicinal Chemistry.
Chemical species originating from oxidatively damaged DNA contribute to the composition of the endogenous exposome. These endogenous exposome may also form biological adducts that have implications in disease development. Identifying DNA adducts are crucial in understanding the etiology of disease states and manifestations of aging. This research seeks to determine if DNA damage contributes to the endogenous exposome through the formation of reactive intermediates. Reactive oxygen species that result from oxidative stress generate carbon-centered radicals in DNA. These radicals result in strand breaks, which liberate small molecules that can be further metabolized into unwanted compounds that maybe mutagenic or carcinogenic. Radicals generated at the 5' carbon (C5') of the 2-deoxyribose moiety result in a 5' aldehyde formation. Consequently, a deoxynucleoside intermediate, or 3',4'-didehydro-3'-deoxy-5'-oxothymidine (ddoT) is formed when the oligonucleotide with 5' aldehyde degrades to a small molecule and a phosphorylated oligomer. ddoT is a reactive molecule proposed to form adducts with constituents of the cellular environment. In this work, properties of ddoT, including its half-life and the conversion to furfural and thymine, were studied. In addition, we examined the reactivity and the viability of ddoT with low molecular weight thiols (glutathione, cysteine, N-acetylcysteine) and coenzyme A as well as developing analytical methods for detections. Glutathione, N-acetylcysteine, coenzyme A, and cysteine successfully formed adducts via Michael addition to ddoT, as evidenced by LC-MS analysis. The study also reveals the dimerization of ddoT in the presence of cysteine. This information will be useful in identifying ddoT adducts to confirm the formation of ddoT as a constituent of the endogenous exposome.
Amanda Bryant-Friedrich, Ph.D. (Committee Chair)
Meng-Cheh Liu, Ph.D. (Committee Member)
Zahoor Shah, Ph.D. (Committee Member)
L.M. Viranga Tillekeratne, Ph.D. (Committee Member)
141 p.
Biochemistry; Biomedical Research; Pharmacy Sciences
Endogenous exposome, DNA damage

Recommended Citations

Citations

  • Cho, S. H. (n.d.). DNA Adducts from 5'-Aldehyde Lesions and their Contributions to the Endogenous Exposome [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1556887150041774

    APA Style (7th edition)

  • Cho, Shin. DNA Adducts from 5'-Aldehyde Lesions and their Contributions to the Endogenous Exposome. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1556887150041774.

    MLA Style (8th edition)

  • Cho, Shin. "DNA Adducts from 5'-Aldehyde Lesions and their Contributions to the Endogenous Exposome." Doctoral dissertation, University of Toledo. Accessed APRIL 18, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1556887150041774

    Chicago Manual of Style (17th edition)

toledo1556887150041774
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