N6-(Deoxy-D-Erythro-Pentofuranosyl)-2,6-Diamino-3,4-Dihydro-4-Oxo-5-N-Methylformamido-Pyrimidine (MeFapy-dG) is a deoxyribonucleic acid lesion that has been hypothesized to be induced by methylating chemotherapeutic agents. MeFapy-dG is known to block DNA replication, ultimately leading to a diverse mutagenic profile dependent on the sequence context. 8-(Deoxyguanosin-N2-yl)-1-Aminopyrene (N2-AP-dG) is a bulky DNA adduct that is a product of 1-nitropyrene (1-NP) nitroreduction. 1-NP is a prevalent chemical carcinogen found in diesel exhaust, coal fly ash, and other environmental pollutants. Previous research demonstrated that N2-AP-dG stalls replication with Dpo4 with the potential to induce various mutations. Both MeFapy-dG and N2-AP-dG were studied in the structural context using Nuclear Magnetic Resonance Spectroscopy (NMR). In the case of MeFapy-dG, important cross-peaks were located in the NMR spectra providing structural evidence of the ?- and ?-anomers, indicating that both populations were present in solution. Furthermore, the N2-AP-dG unmodified duplex was characterized, demonstrating that the unmodified sequence context adopted normal B-type DNA. The modified N2-AP-dG NMR spectra provided evidence that the adduct was oriented in the minor groove of the DNA duplex, pointing in the 3รข direction of the modified strand, with minimal perturbation of the global DNA structure.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03252016-113945 |
| Date | 25 March 2016 |
| Creators | Bowen, Ryan Scott |
| Contributors | Carmelo J. Rizzo, Michael P. Stone |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03252016-113945/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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