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

Nidhi Jain, Srinivasarao Meneni, Vipin Jain, Bongsup P. Cho

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Abstract

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 (ICD290-360nm), 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 ICD290-360 on both temperature and salt concentration and could be extended to the arylamine food mutagens that are biologically relevant in humans.

Original languageEnglish (US)
Pages (from-to)1628-1637
Number of pages10
JournalNucleic acids research
Volume37
Issue number5
DOIs
StatePublished - 2009

Bibliographical note

Funding Information:
We are grateful to the National Institutes of Health (CA098296) for their financial support for this work. This research was also made possible in part by the use of the Rhode Island INBRE Research Core Facility, which is supported by the NCRR/NIH (P20 RR-16457). Funding for open access charge: National Institutes of Health (CA098296).

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