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Title page for ETD etd-06032008-181621

Type of Document Dissertation
Author Brown, Kyle Lamar
Author's Email Address kyle.l.brown@vanderbilt.edu
URN etd-06032008-181621
Title Structural Studies of Fluxional Lesions in Deoxyribonucleic Acid
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Michael P. Stone Committee Chair
Andrzej M. Krezel Committee Member
Brian O. Bachmann Committee Member
F. Peter Guengerich Committee Member
Terry P. Lybrand Committee Member
  • DNA damage
  • NMR
  • Formamidopyrimidine
  • Aflatoxin B1
  • Thymine Glycol
  • DNA -- Structure
Date of Defense 2008-05-21
Availability unrestricted
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.
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