Influence of flanking sequence context on the conformational flexibility of aminofluorene-modified dG adduct in dA mismatch DNA duplexes

When positioned opposite to a dA in a DNA duplex, the prototype arylamineDNA 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 NGN/NAN dA mismatch duplexes (G FAF, N G, A, C, T) exhibited strongly positive induced circular dichroism in the 290360 nm range (ICD290360 nm), which supports the W conformation. The ICD290360 nm intensities were the greatest for duplexes with a 3-flanking T. The AGN duplex series showed little adduct-induced destabilization. An exception was the AGT duplex, which displayed two well-resolved signals in the F-19 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 TGT duplex, which exhibited greater lesion flexibility and nucleotide excision repair recognition. Adduct conformational heterogeneity decreased in order of TGT AGT CGT AGA AGG AGC. 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.