Transcriptional mutagenesis mediated by 8-oxoG induces translational errors in mammalian cells
Transcriptional mutagenesis mediated by 8-oxoG induces translational errors in mammalian cells
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DOI：
10.1073/pnas.1718363115
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发表时间：
2018-04-17
影响因子：
11.1
通讯作者：
Cai, Jian-Ping
中科院分区：
文献类型：
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作者：
Dai, Da-Peng;Gan, Wei;Cai, Jian-Ping
在哺乳动物细胞内形成的活性氧可以在mRNA中产生8-oxo-7,8-二氢鸟嘌呤（8-oxoG），在基因表达过程中导致碱基错配。在这里，我们发现在mth1敲低的细胞中给予8-oxoGTP导致mRNA中8-oxoG含量增加。在这种情况下，报告基因荧光素酶的琥珀色突变被抑制。使用第二代测序技术，我们发现当提供8-oxoGTP时，荧光素酶转录物预分配位点的U-to-G变化增加。此外，RNA中8-oxoG含量的增加诱导了表达淀粉样蛋白前体蛋白的细胞中可聚集淀粉样蛋白β肽的积累。我们的研究结果表明，mRNA中8-oxoG的积累可以改变哺乳动物细胞中蛋白质的合成。需要进一步的工作来评估这些发现在正常生理条件下的意义。
Reactive oxygen species formed within the mammalian cell can produce 8-oxo-7,8-dihydroguanine (8-oxoG) in mRNA, which can cause base mispairing during gene expression. Here we found that administration of 8-oxoGTP in MTH1-knockdown cells results in increased 8-oxoG content in mRNA. Under this condition, an amber mutation of the reporter luciferase is suppressed. Using second-generation sequencing techniques, we found that U-to-G changes at preassigned sites of the luciferase transcript increased when 8-oxoGTP was supplied. In addition, an increased level of 8-oxoG content in RNA induced the accumulation of aggregable amyloid beta peptides in cells expressing amyloid precursor protein. Our findings indicate that 8-oxoG accumulation in mRNA can alter protein synthesis in mammalian cells. Further work is required to assess the significance of these findings under normal physiological conditions.