Aromatic chemical carcinogens can undergo enzymatic transformations to produce a range of electrophilic species that attach covalently to the C8-site of 2′-deoxyguanosine (dG) to afford C8-dG adducts. The most studied C8-dG adducts are formed from arylamines and contain a N-linkage separating the dG from the C8-aryl moiety. Other carcinogenic species result in direct aryl ring attachment to the dG moiety, resulting in C-linked adducts. The resulting C-linked adducts have reduced conformational flexibility compared to the corresponding N-linked C8-dG adducts, which can alter their orientation in the DNA duplex. Described herein are structural studies of a fluorescent C-linked 4-fluorobiphenyl-dG (FBP-dG) that has been incorporated into the reiterated G₃-postion of the 12-mer NarI sequence and those containing other 5′-flanking nucleobases. FBP-dG displays a strong preference for adopting a syn conformation in the fully paired NarI duplex to produce an intercalated structure that exhibits stacking interactions between the C-linked biphenyl and the flanking bases. FBP-dG is also shown to significantly stabilize the slippage mutagenic intermediate (SMI) duplex containing the lesion and 5′-flanking base within a 2-base bulge. FBP-dG exhibits fluorescence sensitivity to SMI duplex formation that can readily distinguish it from the fully paired duplex. Molecular dynamics simulations and optical spectroscopy for the NarI oligonucleotides containing the C-linked FBP-dG predict increased rigidity of the biphenyl in the syn conformation. The greater propensity to generate the promutagenic syn conformation for the C-linked FBP-dG adduct compared to the N-linked 4-aminobiphenyl-dG adduct (ABP-dG) suggests greater mutagenicity for the C-linked analogue. These results highlight the effect of the adduct linkage type on the conformational properties of adducted DNA. The turn-on emission response of FBP-dG in the SMI duplex may be a powerful tool for monitoring SMI formation in the NarI sequence upon synthesis with DNA polymerases.

中文翻译：

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在Nar I突变热点中C相连的C8-联苯-鸟嘌呤的构象偏好和荧光响应：增强的合成加合物形成的证据。

芳香族化学致癌物可以进行酶促转化，以产生一系列亲电子物质，这些亲电子物质共价附于2'-脱氧鸟苷（dG）的C8位，从而提供C8-dG加合物。研究最多的C8-dG加合物由芳基胺形成，并含有将dG与C8-芳基部分分隔开的N键。其他致癌物质会导致芳基环直接连接至dG部分，从而导致C链加成物。与相应的N-连接的C8-dG加合物相比，所得的C-连接的加合物具有降低的构象柔性，这可以改变它们在DNA双链体中的取向。本文描述的是荧光C键联的4-氟联苯-dG（FBP-dG）的结构研究，该化合物已并入12-mer Nar的重复G _3-位我对含有其他5'侧翼碱基的碱基进行测序。FBP-dG对在完全配对的Nar I双链体中采用syn构象以产生插层结构表现出强烈的偏好，该插层结构表现出C连接联苯与侧翼碱基之间的堆叠相互作用。FBP-dG还显示出可显着稳定滑移诱变中间物（SMI）双链体，该双链体包含2个碱基的凸起内的病变和5'侧翼碱基。FBP-dG对SMI双链体的形成具有荧光敏感性，可以很容易地将其与完全配对的双链体区分开。包含C连接的FBP-dG的Nar I寡核苷酸的分子动力学模拟和光谱学预测联苯在合成物中的刚性增加构象。与N-连接的4-氨基联苯-dG加合物（ABP-dG）相比，C-连接的FBP-dG加合物产生促突变的顺式构象的更大倾向表明，C-连接的类似物具有更大的诱变性。这些结果突出了加合物键类型对加合物DNA的构象性质的影响。SMI双链体中FBP-dG的开启发射响应可能是监测DNA聚合酶合成后在Nar I序列中SMI形成的强大工具。