Disher Kim, Skandalis Adonis
Department of Biological Sciences, Brock University, 500 Glenridge Avenue, St. Catharines, ON L2S 3A1, Canada.
Genome. 2007 Oct;50(10):946-53. doi: 10.1139/g07-074.
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.
大多数人类基因会产生mRNA剪接变体。虽然毫无疑问可变剪接是一种重要的生物学现象，但也很明显一些剪接变体与疾病有关。为了阐明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基因HPRT和POLB的可变剪接。我们的研究表明剪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、无功能的剪接变体的总体频率均增加。至少在POLB中，剪接保真度是p53依赖性的。在没有p53的情况下，POLB剪接变体的频率升高，但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配剪接代表一种新的、重要的基因毒性结果，导致错配剪接的不仅仅是氧化应激诱导的DNA损伤，还有可变剪接机制本身的变化。
