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Nucleic Acids Research Advance Access originally published online on January 16, 2009
Nucleic Acids Research 2009 37(5):1628-1637; doi:10.1093/nar/gkn1063
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Nucleic Acids Research, 2009, Vol. 37, No. 5 1628-1637
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

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 and Bongsup P. Cho*

Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA

*To whom correspondence should be addressed. Tel: +1 401 874 5024; Fax: +1 401 874 5766; Email: bcho{at}uri.edu

Received October 16, 2008. Revised December 8, 2008. Accepted December 16, 2008.

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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