Investigation of Oxidative DNA Damage from Ionizing Radiation
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University of Toledo Health Science Campus / OhioLINK
2012
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=mco1349377002 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-mco13493770022021-08-03T05:38:54Z Investigation of Oxidative DNA Damage from Ionizing Radiation Abdallah, Suaad Audat Chemical Engineering Chemistry <p>Oxidative damage to deoxyribonucleic acids (DNA) caused by the direct and indirect effect of ionizing radiation and endogenously produced reactive oxygen species (ROS) can lead to mutations, carcinogenesis and cell death. Damage from ionizing radiation is partially produced by secondary low energy electrons (LEEs) that form along the ionization track. Although it has been established that LEEs can result in the formation of single and double strand breaks, the mechanism of formation of these associated lesions has not been established. It has been shown that addition of low energy electrons to DNA components leads to the formation of transient radical anions that undergo bond cleavage by dissociative electron attachment. The formation of these reactive intermediates causes the generation of carbon-centered radicals on the sugar moiety. Therefore, it is believed that carbon-centered radicals play a fundamental role in this process. One of the intermediates formed is the C2',3'-dideoxythymidinyl radical (102). The goal of this project is to investigate the fate of the C2',3'-dideoxy-C3'-thymidinyl radical in DNA, an intermediate of DNA-LEE interactions. Synthesis of α- and β-C3'-deoxy-3'-pivaloylthymidine (101 and 103, respectively) as radical precursors of this intermediate has been completed and their efficiencies in radical generation has been evaluated. Through photolysis (λ ¿¿¿¿¿¿¿ 320 nm) of these modified thymidines under anaerobic conditions, the radical of interest (102) was generated in the case of α-C3'-deoxy-3'-pivaloylthymidine (103). These findings contribute to the elucidation of the mechanistic pathways of oxidative damage to DNA by LEEs.</p><p>Oxidative damage caused by reactive oxygen species, generated from the ionization of water molecules surrounding DNA or from endogenous sources, result in formation of single and double strand breaks. The hydroxyl radical is capable of damaging the sugar phosphate backbone by abstracting hydrogen atoms from the deoxyribose moiety of DNA leading to formation of single and double strand breaks. These strand breaks are associated with the formation of electrophilic fragments capable of reaction with local nucleophiles to form DNA adducts. Since the 5'- hydrogens of deoxyribose in B-form DNA are the most accessible to solvent, they are highly vulnerable to abstraction. This event leads to the formation of the C5'-radical. Under aerobic conditions and in the presence of thiol the radical forms strand breaks terminated with a 5'-aldehyde moiety and a 3'-phosphate moiety. Oligonucleotides containing a 5'-aldehyde moiety such as 36, are unstable and undergoe elimination to deliver the aromatic compound furfural (67). It was shown that furfural can form an adduct with adenine in DNA. The goal of this project is to investigate the stability and reactivity of oligonucleotides containing a 5'-aldehyde lesion and its degradation products under physiological conditions. The half-life of oligonucleotides containing a 5'-aldehyde lesion was determined to be 96 hours in single-stranded DNA. The half-life of 3',4'-didehydro-2',3'-dideoxy-5'-oxothymidine (66) was determined to be 13 hours under physiological conditions. These experiments help to explain the types of adducts that form as a result of oxidative damage. These adducts can be used as biomarkers for early detection of disease such as cancer.</p> 2012 English text University of Toledo Health Science Campus / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=mco1349377002 http://rave.ohiolink.edu/etdc/view?acc_num=mco1349377002 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
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NDLTD |
| topic |
Chemical Engineering Chemistry |
| spellingShingle |
Chemical Engineering Chemistry Abdallah, Suaad Audat Investigation of Oxidative DNA Damage from Ionizing Radiation |
| author |
Abdallah, Suaad Audat |
| author_facet |
Abdallah, Suaad Audat |
| author_sort |
Abdallah, Suaad Audat |
| title |
Investigation of Oxidative DNA Damage from Ionizing Radiation |
| title_short |
Investigation of Oxidative DNA Damage from Ionizing Radiation |
| title_full |
Investigation of Oxidative DNA Damage from Ionizing Radiation |
| title_fullStr |
Investigation of Oxidative DNA Damage from Ionizing Radiation |
| title_full_unstemmed |
Investigation of Oxidative DNA Damage from Ionizing Radiation |
| title_sort |
investigation of oxidative dna damage from ionizing radiation |
| publisher |
University of Toledo Health Science Campus / OhioLINK |
| publishDate |
2012 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=mco1349377002 |
| work_keys_str_mv |
AT abdallahsuaadaudat investigationofoxidativednadamagefromionizingradiation |
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1719423016239104000 |