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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Distinct mechanisms of cis-syn thymine dimer bypass by Dpo4 and DNA polymerase eta
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Distinct mechanisms of cis-syn thymine dimer bypass by Dpo4 and DNA polymerase eta

机译：Dpo4和DNA聚合酶eta顺式-胸腺嘧啶二聚体旁路的不同机制

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摘要

UV-light-induced cyclobutane pyrimidine dinners (CPDs) present a severe block to synthesis by replicative DNA polymerases (Pols), whereas Pol eta promotes proficient and error-free replication through CPDs. Although the archael Dpo4, which, like Pol eta, belongs to the Y family of DNA Pols, can also replicate through a CPD, it is much less efficient than Pol eta. The x-ray crystal structure of Dpo4 complexed with either the 3'-thymine (T) or the 5' T of a cis-syn TT dinner has indicated that, whereas the 3' T of the dimer forms a Watson-Crick base pair with the incoming dideoxy ATP, the 5' T forms a Hoogsteen base pair with the dideoxy ATP in syn conformation. Based upon these observations, a similar mechanism involving Hoogsteen base pairing of the 5'T of the dimer with the incoming A has been proposed for Pol eta. Here we examine the mechanisms of CPD bypass by Dpo4 and Pol eta using nucleoticle analogs that specifically disrupt the Hoogsteen or Watson-Crick base pairing. Our results show that both Dpo4 and Pol eta incorporate dATP opposite the 5' T of the CPD via Watson-Crick base pairing and not by Hoogsteen base pairing. Furthermore, opposite the 3' T of the dinner, the two Pols differ strikingly in the mechanisms of dATP incorporation, with Dpo4 incorporating opposite an abasic-like intermediate and Pol eta using the normal Watson-Crick base pairing. These observations have important implications for the mechanisms used for the inefficient vs. efficient bypass of CPDs by DNA Pols.
机译：紫外线诱导的环丁烷嘧啶粗粉（CPD）严重阻碍了复制性DNA聚合酶（Pols）的合成，而Pol eta促进了CPD的熟练且无错复制。尽管像Pol eta一样属于DNA Pols Y家族的原始Dpo4也可以通过CPD复制，但效率远低于Pol eta。 Dpo4的x射线晶体结构与顺式syn-TT晚餐的3'-胸腺嘧啶（T）或5'T络合表明，而二聚体的3'T形成Watson-Crick碱基对与引入的双脱氧ATP一起，5'T与双脱氧ATP以顺式构象形成Hoogsteen碱基对。基于这些观察，对于Poleta已经提出了一种类似的机制，其涉及二聚体的5'T的Hoogsteen碱基配对与输入的A。在这里，我们使用特异性破坏Hoogsteen或Watson-Crick碱基配对的核类似物，研究了Dpo4和Pol eta通过CPD旁路的机制。我们的结果表明，Dpo4和Pol eta均通过Watson-Crick碱基配对而非Hoogsteen碱基配对掺入了与CPD 5'T相对的dATP。此外，在晚餐的3'T对面，两个Pol在dATP掺入的机理上存在显着差异，其中Dpo4在无碱基样中间体的对面掺入，而Pol eta使用正常的Watson-Crick碱基配对。这些观察结果对DNA Pols对CPD进行低效率与有效旁路的机制具有重要意义。

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