Solution structure of an 11-mer duplex containing the 3,N-4-ethenocytosineadduct opposite 2 '-deoxycytidine: Implications for the recognition of exocyclic lesions by DNA glycosylases
D. Cullinan et al., Solution structure of an 11-mer duplex containing the 3,N-4-ethenocytosineadduct opposite 2 '-deoxycytidine: Implications for the recognition of exocyclic lesions by DNA glycosylases, J MOL BIOL, 296(3), 2000, pp. 851-861
Lipid peroxidation products, as well as the metabolic products of vinyl chl
oride, react with cellular DNA producing the mutagenic adduct 3,N-4-etheno-
2'-deoxycytidine (epsilon dC), along with several other exocyclic derivativ
es. High-resolution NMR spectroscopy and restrained molecular dynamics simu
lations were used to establish the solution structure of an Il-mer duplex c
ontaining an epsilon dC . dC base-pair at its center. The NMR data suggeste
d a regular right-handed helical structure having all residues in the anti
orientation around the glycosydic torsion angle and Watson-Crick alignments
for all canonical base-pairs of the duplex. Restrained molecular dynamics
generated a three-dimensional model in excellent agreement with the spectro
scopic data. The (epsilon dC . dC)-duplex structure is a regular right-hand
ed helix with a slight bend at the lesion site and no severe distortions of
the sugar-phosphate backbone. The epsilon dC adduct and its partner dC wer
e displaced towards opposite grooves of the helix, resulting in a lesion-co
ntaining base-pair that was highly sheared but stabilized to some degree by
the formation of a single hydrogen bond. Such a sheared base-pair alignmen
t at the lesion site was previously observed for epsilon dC . dG and epsilo
n dC . T duplexes, and was also present in the crystal structures of duplex
es containing dG . T and dG . U mismatches. These observations suggest the
existence of a substrate structural motif that may be recognized by specifi
c DNA glycosylases during the process of base excision repair. (C) 2000 Aca
demic Press.