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Evidence of the modulation of mRNA splicing fidelity in humans by oxidative stress and p53

机译:氧化应激和p53调节人类mRNA剪接保真度的证据

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The majority of human genes generate mRNA splice variants and while there is little doubt that alternative splicing is an important biological phenomenon, it has also become apparent that some splice variants are associated with disease. To elucidate the molecular mechanisms responsible for generating aberrant splice variants, we have investigated alternative splicing of the human genes HPRT and POLB following oxidative stress in different genetic backgrounds. Our study revealed that splicing fidelity is sensitive to oxidative stress. Following treatment of cells with H2O2, the overall frequency of aberrant, unproductive splice variants increased in both loci. At least in POLB, splicing fidelity is p53 dependent. In the absence of p53, the frequency of POLB splice variants is elevated but oxidative stress does not further increase the frequency of splice variants. Our data indicate that mis-splicing following oxidative stress represents a novel and significant genotoxic outcome and that it is not simply DNA lesions induced by oxidative stress that lead to mis-splicing but changes in the alternative splicing machinery itself.
机译:大多数人类基因均会产生mRNA剪接变体,尽管毫无疑问,选择性剪接是一种重要的生物学现象,但显然某些剪接变体与疾病有关。为了阐明负责产生异常剪接变体的分子机制,我们研究了在不同遗传背景下氧化应激后人类基因HPRT和POLB的选择性剪接。我们的研究表明,拼接保真度对氧化应激敏感。用H2O2处理细胞后,两个基因座中异常,无效的剪接变体的总频率都增加了。至少在POLB中,拼接保真度取决于p53。在不存在p53的情况下,POLB剪接变体的频率升高,但是氧化应激不会进一步增加剪接变体的频率。我们的数据表明,氧化应激后的错接代表了一种新颖而重要的遗传毒性结果,不仅仅是氧化应激诱导的DNA损伤导致错接,而且替代剪接机制本身也发生了变化。

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