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Selective Recognition of Conformation-Specific Arylamine-DNA Adduct in Frameshift Model by [Ru(phen)2(dppz)]2.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-02-17 , DOI: 10.1021/acs.chemrestox.9b00453 David Paul Elisa Dayanidhi 1 , Nandhini Thangavel 1 , Vaidyanathan Vaidyanathan Ganesan 1
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-02-17 , DOI: 10.1021/acs.chemrestox.9b00453 David Paul Elisa Dayanidhi 1 , Nandhini Thangavel 1 , Vaidyanathan Vaidyanathan Ganesan 1
Affiliation
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Arylamine modification of guanine base at the G3 position in the NarI sequence (-G1G2CG3CC-) causes a frameshift mutation. Polymerase and 19F NMR studies have shown that the next flanking base at the 3' position to the G3 adduct modulates the mutational outcome because of its different conformations. Here, we have studied the interaction of the 16-mer NarI sequence (5'-CTCTCG1G2CG3CXATCAC-3') (G3 = N-acetyl-2-aminofluorene (AAF)-dG and X is either C or T) with [Ru(phen)2(dppz)]2+ (phen = 1,10-phenanthroline and dppz = dipyrido[3,2-a:2',3'-c]phenazine). Interaction studies between isomers of Ru(II) and two oligonucleotide models, viz., (a) full duplex, and (b) slipped mutagenic intermediate (SMI), have been carried out. Luminescence studies reveal that the sensitivity of Ru(II) with an adduct increases 2- to 3-fold compared to that of control in full duplex. In SMI, the sensitivity of Ru(II) varies with the next flanking base and in the order of -GAAFCC > -GAAFCT. Microscale thermophoretic data reveal that in full duplex Λ-Ru binds to -GAAFCT- by 13- and 4-fold stronger than its control and -GAAFCC-, respectively. In SMI, Δ-Ru binds to -GAAFCC- (41% stacked (S) conformer) by 3-fold while -GAAFCT- (86% major groove (B) conformer) weakens the binding of Λ-Ru by 250-fold compared to the control. The results presented here reveal that the binding of Ru(II) not only depends on conformations of the AAF-dG adduct but also is isomer-centric and might be helpful in determining the conformational heterogeneity of other covalent aryl/heterocyclic amine-DNA adducts.
中文翻译：
通过[Ru（phen）2（dppz）] 2选择性识别移码模型中特定构象的芳胺-DNA加合物。
NarI序列（-G1G2CG3CC-）中G3位置的鸟嘌呤碱基的芳基胺修饰导致移码突变。聚合酶和19F NMR研究表明，由于G3加合物的不同构象，其下一个侧翼碱基位于G3加合物的3'位置，可调节突变结果。在这里，我们研究了16-mer NarI序列（5'-CTCTCG1G2CG3CXATCAC-3'）（G3 = N-乙酰-2-氨基芴（AAF）-dG，X为C或T）与[Ru（ phen）2（dppz）] 2+（phen = 1,10-菲咯啉，dppz =二吡啶基[3,2-a：2'，3'-c]吩嗪）。Ru（II）的异构体与两个寡核苷酸模型，即（a）全双链体和（b）突变诱变中间体（SMI）之间的相互作用研究已经进行。发光研究表明，与全双工中的对照相比，Ru（II）与加合物的敏感性增加了2到3倍。在SMI中，Ru（II）的敏感性随下一个侧翼碱基的变化而变化，其顺序为-GAAFCC> -GAAFCT。微量热泳数据表明，在全双链体中，-Ru与-GAAFCT-的结合强度分别比其对照和-GAAFCC-高13倍和4倍。在SMI中，Δ-Ru与-GAAFCC-（41％堆叠（S）构象异构体）结合3倍，而-GAAFCT-（86％主沟（B）构象异构体）与Λ-Ru的结合弱250倍到控制。此处给出的结果表明，Ru（II）的结合不仅取决于AAF-dG加合物的构象，而且还取决于异构体，并且可能有助于确定其他共价芳基/杂环胺-DNA加合物的构象异质性。
更新日期：2020-02-17
中文翻译：
通过[Ru（phen）2（dppz）] 2选择性识别移码模型中特定构象的芳胺-DNA加合物。
NarI序列（-G1G2CG3CC-）中G3位置的鸟嘌呤碱基的芳基胺修饰导致移码突变。聚合酶和19F NMR研究表明，由于G3加合物的不同构象，其下一个侧翼碱基位于G3加合物的3'位置，可调节突变结果。在这里，我们研究了16-mer NarI序列（5'-CTCTCG1G2CG3CXATCAC-3'）（G3 = N-乙酰-2-氨基芴（AAF）-dG，X为C或T）与[Ru（ phen）2（dppz）] 2+（phen = 1,10-菲咯啉，dppz =二吡啶基[3,2-a：2'，3'-c]吩嗪）。Ru（II）的异构体与两个寡核苷酸模型，即（a）全双链体和（b）突变诱变中间体（SMI）之间的相互作用研究已经进行。发光研究表明，与全双工中的对照相比，Ru（II）与加合物的敏感性增加了2到3倍。在SMI中，Ru（II）的敏感性随下一个侧翼碱基的变化而变化，其顺序为-GAAFCC> -GAAFCT。微量热泳数据表明，在全双链体中，-Ru与-GAAFCT-的结合强度分别比其对照和-GAAFCC-高13倍和4倍。在SMI中，Δ-Ru与-GAAFCC-（41％堆叠（S）构象异构体）结合3倍，而-GAAFCT-（86％主沟（B）构象异构体）与Λ-Ru的结合弱250倍到控制。此处给出的结果表明，Ru（II）的结合不仅取决于AAF-dG加合物的构象，而且还取决于异构体，并且可能有助于确定其他共价芳基/杂环胺-DNA加合物的构象异质性。
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