Date of Original Version
Biomedical and Pharmaceutical Sciences
When positioned opposite to a dA in a DNA duplex, the prototype arylamine-DNA adduct [N-(2'-deooxyguanosin-yl)-7-flouro-2-aminoflourene(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*NAN dA mismatch duplexes (G*=FAF, N=G, A, C, T) exhibited strongly positive induced circular dichroism in the 290-360nm range (ICD290-360nm), which supports the W conformation. The ICD290-360nm 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 ICD260-360 on both temperature and salt concentration and could be extended to the arylamine food mutagens that are biologically relevant in humans.
Nidhi Jain, Srinivasarao Meneni, Vipin Jain, Bongsup P. Cho; Influence of flanking sequence context on the conformational flexibility of aminofluorene-modified dG adduct in dA mismatch DNA duplexes, Nucleic Acids Research, Volume 37, Issue 5, 1 April 2009, Pages 1628–1637, https://doi.org/10.1093/nar/gkn1063
Available at: http://dx.doi.org/10.1093/nar/gkn1063
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