dc.creator | Brown, Kyle Lamar | |
dc.date.accessioned | 2020-08-22T17:02:34Z | |
dc.date.available | 2010-06-06 | |
dc.date.issued | 2008-06-06 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-06032008-181621 | |
dc.identifier.uri | http://hdl.handle.net/1803/12455 | |
dc.description.abstract | This dissertation involves the structural and equilibrium studies of three DNA lesions: aflatoxin B1 formamidopyrimidine, methyl formamidopyrimidine, and thymine glycol. Studies of the methyl formamidopyrimidine (Me-dGuo-FAPY) found that the lesion exists as a mixture of alpha and beta anomers in the nucleotide 5'-CTATXATTCA-3'. Each anomer was in a 1:1 equilibrium and was a mix of rotamers. Aflatoxin B1 formamidopyrimidine adduct (AFB1-FAPY) was a mixture of alpha and beta anomers (2:1) in 5'-CTATXATTCA-3'; only the beta anomer was observed in 5'-CTATXATTCA-3'•5'-TGAATCATAG-3'. The alpha anomer destabilized duplex DNA by 13 °C while beta anomer stabilized the duplex 14 °C. Duplex stabilization of beta-AFB1-FAPY modified DNA was attributed in part to favorable stacking interactions with the complementary strand. Destabilization of alpha-AFB1-FAPY modified DNA was attributed to abnormal backbone geometry and disrupted stacking patterns with neighboring base pairs. The E geometrical isomer of the formamide was stabilized by an intra-strand hydrogen bond with the 3'-adenine N6 amino group; stabilization was reduced in single strand DNA so that the Z geometrical isomer was observed. In structural studies of AFB1-FAPY in oligonucleotides only the Ra atropisomer was observed. The alpha anomer of cis-5R,6S-thymine glycol lesion was not observed in single strand or duplex DNA. However, equilibrium of cis-5R,6S-thymine glycol with its trans epimer 5R,6R was 7:3 when base paired opposite adenine; only 5R,6S was observed when base paired with guanine. Thermodynamic analysis of cis-5R,6S-thymine glycol opposite adenine and guanine indicated that both lesions destabilize duplex DNA by 13 °C. | |
dc.format.mimetype | application/pdf | |
dc.subject | DNA damage | |
dc.subject | NMR | |
dc.subject | Formamidopyrimidine | |
dc.subject | Aflatoxin B1 | |
dc.subject | Thymine Glycol | |
dc.subject | DNA -- Structure | |
dc.title | Structural Studies of Fluxional Lesions in Deoxyribonucleic Acid | |
dc.type | dissertation | |
dc.contributor.committeeMember | Brian O. Bachmann | |
dc.contributor.committeeMember | F. Peter Guengerich | |
dc.contributor.committeeMember | Terry P. Lybrand | |
dc.contributor.committeeMember | Andrzej M. Krezel | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Chemistry | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2010-06-06 | |
local.embargo.lift | 2010-06-06 | |
dc.contributor.committeeChair | Michael P. Stone | |