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首页> 外文期刊>Molecular and Cellular Biology >Replication past a trans-4-Hydroxynonenal Minor-Groove Adduct by the Sequential Action of Human DNA Polymerases ι and κ
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Replication past a trans-4-Hydroxynonenal Minor-Groove Adduct by the Sequential Action of Human DNA Polymerases ι and κ

机译：通过人类DNA聚合酶η和κ的顺序作用复制通过反式4-羟基壬醛小沟加合物

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The X-ray crystal structure of human DNA polymerase ι (Polι) has shown that it differs from all known Pols in its dependence upon Hoogsteen base pairing for synthesizing DNA. Hoogsteen base pairing provides an?elegant mechanism for synthesizing DNA opposite minor-groove adducts that present a severe block to synthesis by replicative DNA polymerases. Germane to this problem, a variety of DNA adducts form at the N2 minor-groove position of guanine. Previously, we have shown that proficient and error-free replication through the γ-HOPdG (γ-hydroxy-1,N2-propano-2′-deoxyguanosine) adduct, which is formed from the reaction of acrolein with the N2 of guanine, is mediated by the sequential action of human Polι and Polκ, in which Polι incorporates the nucleotide opposite the lesion site and Polκ carries out the subsequent extension reaction. To test the general applicability of these observations to other adducts formed at the N2 position of guanine, here we examine the proficiency of human Polι and Polκ to synthesize past stereoisomers of trans-4-hydroxy-2-nonenal-deoxyguanosine (HNE-dG). Even though HNE- and acrolein-modified dGs share common structural features, due to their increased size and other structural differences, HNE adducts are potentially more blocking for replication than γ-HOPdG. We show here that the sequential action of Polι and Polκ promotes efficient and error-free synthesis through the HNE-dG adducts, in which Polι incorporates the nucleotide opposite the lesion site and Polκ performs the extension reaction.
机译：人DNA聚合酶I（PolI）的X射线晶体结构已经显示出它与所有已知的Pols的不同之处在于其对用于合成DNA的Hoogsteen碱基配对的依赖性。 Hoogsteen碱基配对为合成与小沟加合物相对的DNA提供了良好的机制，这些小沟加合物通过复制DNA聚合酶为合成提供了严重的障碍。与这个问题密切相关，鸟嘌呤的N 2 小槽位置会形成多种DNA加合物。以前，我们已经证明可以通过γ-HOPdG（γ-羟基-1， N 2 -丙烷2'-脱氧鸟苷）加合物进行精确无误的复制，它是由丙烯醛与鸟嘌呤的N 2 反应形成的，它是由人类Polι和Polκ的顺序作用介导的，其中Polι掺入与病变部位相对的核苷酸，Polκ进行随后的延伸反应。为了测试这些观察结果对鸟嘌呤N 2 位置形成的其他加合物的一般适用性，我们在这里检查了人类Polι和Polκ合成过去的 trans 立体异构体的能力。 -4-羟基-2-壬烯脱氧鸟苷（HNE-dG）。尽管HNE和丙烯醛修饰的dG具有共同的结构特征，但由于它们的尺寸增加和其他结构差异，HNE加合物可能比γ-HOPdG更能阻止复制。我们在此显示，Polι和Polκ的顺序作用通过HNE-dG加合物促进了高效且无错误的合成，其中Pol1掺入了与病变部位相对的核苷酸，Polκ进行了延伸反应。

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