The environmental arylamine mutagens are implicated in the etiology of various sporadic human cancers. Arylamine-modified dG lesions were studied in two fully paired 11-mer duplexes with a-G*CN-sequence context, in which G* is a C8-substituted dG adduct derived from fluorinated analogs of 4-aminobiphenyl (FABP), 2-aminofluorene (FAF) or 2-acetylaminofluorene (FAAF), and N is either dA or dT. The FABP and FAF lesions exist in a simple mixture of 'stacked' (S) and 'B-type' (B) conformers, whereas the N-acetylated FAAF also samples a 'wedge' (W) conformer. FAAF is repaired three to four times more efficiently than FABP and FAF. A simple A-to-T polarity swap in the G*CA/G*CT transition produced a dramatic increase in syn-conformation and resulted in 2-to 3-fold lower nucleotide excision repair (NER) efficiencies in Escherichia coli. These results indicate that lesion-induced DNA bending/thermodynamic destabilization is an important DNA damage recognition factor, more so than the local S/B-conformational heterogeneity that was observed previously for FAF and FAAF in certain sequence contexts. This work represents a novel 3′-next flanking sequence effect as a unique NER factor for bulky arylamine lesions in E. coli.
Bibliographical noteFunding Information:
National Institutes of Health (NIH) [CA098296 to B.C., GM051501 to A.D.M. and CA86927 to Y.Z.]; the National Science Foundation/RI-EPSCoR  and the RI-INBRE core facility supported by National Institutes of Health [P20 RR016457]. Funding for open access charge: NIH/NCI.