Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
Science. 2013 Apr 5;340(6128):82-5. doi: 10.1126/science.1231197.
MicroRNAs (miRNAs) control gene expression through both translational repression and degradation of target messenger RNAs (mRNAs). However, the interplay between these processes and the precise molecular mechanisms involved remain unclear. Here, we show that translational inhibition is the primary event required for mRNA degradation. Translational inhibition depends on miRNAs impairing the function of the eIF4F initiation complex. We define the RNA helicase eIF4A2 as the key factor of eIF4F through which miRNAs function. We uncover a correlation between the presence of miRNA target sites in the 3' untranslated region (3'UTR) of mRNAs and secondary structure in the 5'UTR and show that mRNAs with unstructured 5'UTRs are refractory to miRNA repression. These data support a linear model for miRNA-mediated gene regulation in which translational repression via eIF4A2 is required first, followed by mRNA destabilization.
微小 RNA（miRNA）通过翻译抑制和靶信使 RNA（mRNA）的降解来控制基因表达。然而，这些过程之间的相互作用以及涉及的精确分子机制仍不清楚。在这里，我们表明翻译抑制是 mRNA 降解所必需的主要事件。翻译抑制取决于 miRNA 损害 eIF4F 起始复合物的功能。我们将 RNA 解旋酶 eIF4A2 定义为 miRNA 发挥作用的 eIF4F 的关键因子。我们揭示了存在于 mRNAs 的 3'非翻译区（3'UTR）中的 miRNA 靶位点与 5'UTR 中的二级结构之间的相关性，并表明具有无结构 5'UTR 的 mRNAs 对 miRNA 抑制具有抗性。这些数据支持 miRNA 介导的基因调控的线性模型，其中首先需要通过 eIF4A2 进行翻译抑制，然后是 mRNA 不稳定性。
