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Title page for ETD etd-03282006-151913

Type of Document Dissertation
Author Cho, Young-Jin
Author's Email Address young.j.cho@vanderbilt.edu
URN etd-03282006-151913
Title NMR studies of an α,β-unsaturated aldehyde-derived interstrand carbinolamine DNA cross-link in the 5´-CpG-3´ sequence
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Dr. Michael P. Stone Committee Chair
Dr. Carmelo J. Rizzo Committee Member
Dr. Charse Sanders Committee Member
Dr. Sandra J. Rosenthal Committee Member
Dr. Terry Lybrand Committee Member
  • acrolein
  • NMR
  • interstrand DNA cross-link
  • carbinolamine
  • crotonaldehyde
Date of Defense 2006-03-23
Availability unrestricted
The chemistry of acrolein and crotonaldehyde-derived propano-deoxyguanosine (γ-OH-PdG and α-CH3-γ-OH-PdG) adducts was monitored in the 5´-CpG-3´ sequence within a dodecamer duplex by NMR spectroscopy, in situ, using a series of site-specific 13C- and 15N-edited experiments. One striking phenomenon was the formation of an interstrand DNA cross-link, predominantly a carbinolamine. The cross-link existed in equilibrium with the non-crosslinked aldehyde and its geminal diol hydrate. The ratio of aldehyde/diol increased at higher temperatures. The effects of the pH and complementary bases were examined. Molecular modeling suggested that the carbinolamine linkage should be capable of maintaining Watson-Crick hydrogen bonds at both of the tandem C•G base pairs. In contrast, dehydration of the carbinolamine cross-link to an imine (Schiff base) cross-link, or cyclization of the latter to form a pyrimidopurinone cross-link, was predicted to require disruption of Watson-Crick hydrogen bonds at one or both of the tandem cross-linked C•G base pairs. Structural study of the S-crotonaldehyde-derived dG adduct ring-opened species suggested its slow generation of a cross-link was due to the configuration of the methyl group. The fully reduced R- and S-crotonaldehyde-derived cross-link studies confirm that these cross-links can be accommodated in duplex DNA. The methyl stereochemistry also affects the thermodynamic stability of the reduced cross-links in duplex DNA. The results provide a rationale for the stability of interstrand cross-links formed by acrolein and crotonaldehyde and perhaps other α,β-unsaturated aldehydes. These sequence-specific carbinolamine cross-links are anticipated to interfere with DNA replication and contribute to acrolein- and crotonaldehyde-mediated genotoxicity.
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