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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Translesional DNA Synthesis through a C8-Guanyl Adduct of 2-Amino-1-methyl-6-phenylimidazo45-bpyridine (PhIP) in Vitro
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Translesional DNA Synthesis through a C8-Guanyl Adduct of 2-Amino-1-methyl-6-phenylimidazo45-bpyridine (PhIP) in Vitro

机译：通过2-氨基-1-甲基-6-苯基咪唑并45-b吡啶（PhIP）的C8-胍基加合物进行跨部位DNA合成

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2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine in cooked foods, and is both mutagenic and carcinogenic. It has been suspected that the carcinogenicity of PhIP is derived from its ability to form DNA adducts, principally dG-C8-PhIP. To shed further light on the molecular mechanisms underlying the induction of mutations by PhIP, in vitro DNA synthesis analyses were carried out using a dG-C8-PhIP-modified oligonucleotide template. In this template, the dG-C8-PhIP adduct was introduced into the second G of the TCC GGG AAC sequence located in the 5′ region. This represents one of the mutation hot spots in the rat Apc gene that is targeted by PhIP. Guanine deletions at this site in the Apc gene have been found to be preferentially induced by PhIP in rat colon tumors. DNA synthesis with A- or B-family DNA polymerases, such as Escherichia coli polymerase (pol) I and human pol δ, was completely blocked at the adducted guanine base. Translesional synthesis polymerases of the Y-family, pol η, pol ι, pol κ, and REV1, were also used for in vitro DNA synthesis analyses with the same templates. REV1, pol η, and pol κ were able to insert dCTP opposite dG-C8-PhIP, although the efficiencies for pol η and pol κ were low. pol κ was also able to catalyze the extension reaction from the dC opposite dG-C8-PhIP, during which it often skipped over one dG of the triple dG sequence on the template. This slippage probably leads to the single dG base deletion in colon tumors.
机译：2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）是熟食中含量最高的杂环胺，具有致突变性和致癌性。人们怀疑，PhIP的致癌性源自其形成DNA加合物（主要是dG-C8-PhIP）的能力。为了进一步阐明PhIP诱导突变的分子机制，使用dG-C8-PhIP修饰的寡核苷酸模板进行了体外DNA合成分析。在该模板中，将dG-C8-PhIP加合物引入位于5'区的TCC GGG AAC序列的第二个G中。这代表了PhIP靶向的大鼠Apc基因中的突变热点之一。已经发现在大鼠结肠肿瘤中，PhIP优先诱导Apc基因中该位点的鸟嘌呤缺失。用A或B族DNA聚合酶（例如大肠杆菌聚合酶（pol）I和人polδ）进行的DNA合成在加成的鸟嘌呤碱基上被完全阻断。 Y家族，polη，polι，polκ和REV1的跨病变合成聚合酶也用于具有相同模板的体外DNA合成分析。 REV1，polη和polκ能够插入与dG-C8-PhIP相反的dCTP，尽管p​​olη和polκ的效率较低。 polκ还能够催化来自与dG-C8-PhIP相反的dC的延伸反应，在此过程中，它常常跳过模板上三重dG序列的一个dG。这种滑移可能导致结肠肿瘤中单个dG碱基缺失。

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