Influence of flanking sequence context on the conformational flexibility of aminofluorene-modified dG adduct in dA mismatch DNA duplexes
2009
Jain, Nidhi | Meneni, Srinivasarao | Jain, Vipin | Cho, Bongsup P.
When positioned opposite to a dA in a DNA duplex, the prototype arylamine-DNA adduct [N-(2'-deoxyguanosin-yl)-7-fluoro-2-aminofluorene (FAF)] adopts the so-called 'wedge' (W) conformation, in which the carcinogen resides in the minor groove of the duplex. All 16 FAF-modified 12-mer NG*N/NAN dA mismatch duplexes (G* = FAF, N = G, A, C, T) exhibited strongly positive induced circular dichroism in the 290-360 nm range (ICD₂₉₀₋₃₆₀ nm), which supports the W conformation. The ICD₂₉₀₋₃₆₀ nm intensities were the greatest for duplexes with a 3'-flanking T. The AG*N duplex series showed little adduct-induced destabilization. An exception was the AG*T duplex, which displayed two well-resolved signals in the ¹⁹F NMR spectra. This was presumably due to a strong lesion-destabilizing effect of the 3'-T. The flanking T effect was substantiated further by findings with the TG*T duplex, which exhibited greater lesion flexibility and nucleotide excision repair recognition. Adduct conformational heterogeneity decreased in order of TG*T > AG*T > CG*T > AG*A > AG*G > AG*C. The dramatic flanking T effect on W-conformeric duplexes is consistent with the strong dependence of the ICD₂₉₀₋₃₆₀ on both temperature and salt concentration and could be extended to the arylamine food mutagens that are biologically relevant in humans.
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