Base-Displaced Intercalated Conformation of the 2-Amino-3-methylimidazo[4,5-f]quinoline N2-dG DNA Adduct Positioned at the Nonreiterated G1 in the NarI Restr

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• 作者：Kallie M. Stavros ; Edward K. Hawkins ; Carmelo J. Rizzo ; Michael P. Stone
• 刊名：Chemical Research in Toxicology
• 出版年：2015
• 出版时间：July 20, 2015
• 年：2015
• 卷：28
• 期：7
• 页码：1455-1468
• 全文大小：623K
• ISSN：1520-5010

文摘

The conformation of an N²-dG adduct arising from the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a potent food mutagen, was determined in 5鈥?d(C¹T²C³X⁴G⁵C⁶G⁷C⁸C⁹A¹⁰T¹¹C¹²)-3鈥?5鈥?d(G¹³A¹⁴T¹⁵G¹⁶G¹⁷C¹⁸G¹⁹C²⁰C²¹G²²A²³G²⁴)-3鈥? X = N²-dG-IQ, in which the modified nucleotide X⁴ corresponds to G¹ in the 5鈥?d(G¹G²CG³CC)-3鈥?NarI restriction endonuclease site. Circular dichroism (CD) revealed blue shifts relative to the unmodified duplex, consistent with adduct-induced twisting, and a hypochromic effect for the IQ absorbance in the near UV region. NMR revealed that the N²-dG-IQ adduct adopted a base-displaced intercalated conformation in which the modified guanine remained in the anti conformation about the glycosidic bond, the IQ moiety intercalated into the duplex, and the complementary base C²¹ was displaced into the major groove. The processing of the N²-dG-IQ lesion by hpol 畏 is sequence-dependent; when placed at the reiterated G³ position, but not at the G¹ position, this lesion exhibits a propensity for frameshift replication [Choi, J. Y., et al. (2006) J. Biol. Chem., 281, 25297鈥?5306]. The structure of the N²-dG-IQ adduct at the nonreiterated G¹ position was compared to that of the same adduct placed at the G³ position [Stavros, K. M., et al. (2014) Nucleic Acids Res., 42, 3450鈥?463]. CD indicted minimal spectral differences between the G¹ vs G³ N²-dG-IQ adducts. NMR indicated that the N²-dG-IQ adduct exhibited similar base-displaced intercalated conformations at both the G¹ and G³ positions. This result differed as compared to the corresponding C8-dG-IQ adducts placed at the same positions. The C8-dG-IQ adduct adopted a minor groove conformation when placed at position G¹ but a base-displaced intercalated conformation when placed at position G³ in the NarI sequence. The present studies suggest that differences in lesion bypass by hpol 畏 may be mediated by differences in the 3鈥?flanking sequences, perhaps modulating the ability to accommodate transient strand slippage intermediates.