Modeling and molecular mechanical studies of the cis-thymine glycol radiation damage lesion in DNA.
Computer graphics and energy minimization techniques were used to construct a model of DNA containing cis-thymine glycol, an oxidation product of thymine formed in DNA by ionizing radiation. The model simulated an experimental DNA substrate used to study the effects of this lesion on DNA synthesis in vitro. The results derived from the model indicate that cis-thymine glycol lesions introduce localized perturbations of DNA structure. Specifically the model shows that interactions with the neighboring base pair on the 5' side are significantly destabilized by thymine glycol whereas interactions with the 3' base pair are stabilized by the lesion. The magnitude of these effects is modulated by the nucleotide sequence around the lesion, particularly by the nature of the base on the 3' side. The base pair formed between adenine and thymine glycol is energetically stable and shows minimal distortion, suggesting that this lesion retains the ability to direct the insertion of the correct nucleotide during DNA synthesis.
Clark
J M
JM
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510.
Pattabiraman
N
N
Jarvis
W
W
Beardsley
G P
GP
D001483:Base Sequence; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D013237:Stereoisomerism; D013941:Thymine / Q000031:analogs & derivatives*
C029389:thymine glycol; D004247:DNA; D013941:Thymine