Base-Displaced Intercalated Structure of the N-(2鈥?Deoxyguanosin-8-yl)-3-aminobenzanthrone DNA Adduct

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• 作者：Dustin A. Politica ; Chanchal K. Malik ; Ashis K. Basu ; Michael P. Stone
• 刊名：Chemical Research in Toxicology
• 出版年：2015
• 出版时间：December 21, 2015
• 年：2015
• 卷：28
• 期：12
• 页码：2253-2266
• 全文大小：702K
• ISSN：1520-5010

文摘

3-Nitrobenzanthrone (3-NBA), an environmental mutagen found in diesel exhaust and a suspected carcinogen, undergoes metabolic reduction followed by reaction with DNA to form aminobenzanthrone (ABA) adducts, with the major alkylation product being N-(2鈥?deoxyguanosin-8-yl)-3-aminobenzanthrone (C8-dG-ABA). Site-specific synthesis of the C8-dG-ABA adduct in the oligodeoxynucleotide 5鈥?d(GTGCXTGTTTGT)-3鈥?5鈥?d(ACAAACACGCAC)-3鈥? X = C8-dG-ABA adduct, including codons 272鈥?75 of the p53 gene, has allowed for investigation into the structural and thermodynamic properties of this adduct. The conformation of the C8-dG-ABA adduct was determined using NMR spectroscopy and was refined using molecular dynamics (MD) calculations restrained by experimentally determined interproton distance restraints obtained from NOE experiments. The refined structure revealed that the C8-dG-ABA adduct formed a base-displaced intercalated conformation. The adducted guanine was shifted into the syn conformation about the glycosidic bond. The 5鈥? and 3鈥?neighboring base pairs remained intact. While this facilitated 蟺-stacking interactions between the ABA moiety and neighboring bases, the thermal melting temperature (T_m) of the adduct-containing duplex showed a decrease of 11 掳C as compared to the corresponding unmodified oligodeoxynucleotide duplex. Overall, in this sequence, the base-displaced intercalated conformation of the C8-dG-ABA lesion bears similarity to structures of other arylamine C8-dG adducts. However, in this sequence, the base-displaced intercalated conformation for the C8-dG-ABA adduct differs from the conformation of the N²-dG-ABA adduct reported by de los Santos and co-workers, in which it is oriented in the minor groove toward the 5鈥?end of the duplex, with the modified guanine remaining in the anti conformation about the glyosidic torsion angle, and the complementary base remaining within the duplex. The results are discussed in relationship to differences between the C8-dG-ABA and N²-dG-ABA adducts with respect to susceptibility to nucleotide excision repair (NER).