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首页> 外文期刊>Nucleic Acids Research >Processing of thymine glycol in a clustered DNA damage site: mutagenic or cytotoxic.
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Processing of thymine glycol in a clustered DNA damage site: mutagenic or cytotoxic.

机译：在簇状DNA损伤位点中胸腺嘧啶乙二醇的加工：致突变或细胞毒性。

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摘要

Localized clustering of damage is a hallmark of certain DNA-damaging agents, particularly ionizing radiation. The potential for genetic change arising from the effects of clustered damage sites containing combinations of AP sites, 8-oxo-7,8-dihydroguanine (8-oxoG) or 5,6-dihydrothymine is high. To date clusters containing a DNA base lesion that is a strong block to replicative polymerases, have not been explored. Since thymine glycol (Tg) is non-mutagenic but a strong block to replicative polymerases, we have investigated whether clusters containing Tg are highly mutagenic or lead to potentially cytotoxic lesions, when closely opposed to either 8-oxoG or an AP site. Using a bacterial plasmid-based assay and repair assays using cell extracts or purified proteins, we have shown that DNA double-strand breaks (DSBs) arise when Tg is opposite to an AP site, either through attempted base excision repair or at replication. In contrast, 8-oxoG opposite to Tg in a cluster 'protects' against DSB formation but does enhance the mutation frequency at the site of 8-oxoG relative to that at a single 8-oxoG, due to the decisive role of endonucleases in the initial stages of processing Tg/8-oxoG clusters, removing Tg to give an intermediate with an abasic site or single-strand break.
机译：损害的局部聚集是某些DNA破坏剂（尤其是电离辐射）的标志。由包含AP位点，8-oxo-7,8-二氢鸟嘌呤（8-oxoG）或5,6-二氢胸腺嘧啶的组合的聚集损伤位点的作用引起的遗传变化的可能性很高。迄今为止，尚未探索包含DNA碱基病变的簇，所述DNA碱基病变是复制性聚合酶的强力阻断。由于胸腺嘧啶乙二醇（Tg）是非诱变的，但对复制型聚合酶具有很强的阻断作用，因此，当与8-oxoG或AP位点紧密相对时，我们已经研究了含有Tg的簇是高度诱变还是导致潜在的细胞毒性损害。使用基于细菌质粒的测定和使用细胞提取物或纯化的蛋白质进行的修复测定，我们已经表明，当Tg与AP位点相反时，DNA链断裂（DSBs）会通过尝试碱基切除修复或复制而出现。相比之下，簇中与Tg相反的8-oxoG“保护”了DSB的形成，但由于内切核酸酶在果蝇中的决定性作用，相对于单个8-oxoG，它确实提高了8-oxoG的突变频率。在处理Tg / 8-oxoG簇的初始阶段，除去Tg，得到具有无碱基位点或单链断裂的中间体。

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