Ding Xavier C, Grosshans Helge
Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
EMBO J. 2009 Feb 4;28(3):213-22. doi: 10.1038/emboj.2008.275. Epub 2009 Jan 8.
MicroRNAs (miRNAs) repress target genes through a poorly defined antisense mechanism. Cell-free and cell-based assays have supported the idea that miRNAs repress their target mRNAs by blocking initiation of translation, whereas studies in animal models argued against this possibility. We examined endogenous targets of the let-7 miRNA, an important regulator of stem cell fates. We report that let-7 represses translation initiation in Caenorhabditis elegans, demonstrating this mode of action for the first time in an organism. Unexpectedly, although the lin-4 miRNA was previously reported to repress its targets at a step downstream of translation initiation, we also observe repression of translation initiation for this miRNA. This repressive mechanism, which frequently but not always coincides with transcript degradation, requires the GW182 proteins AIN-1 and AIN-2, and acts on several mRNAs targeted by different miRNAs. Our analysis of an expanded set of endogenous miRNA targets therefore indicates widespread repression of translation initiation under physiological conditions and establishes C. elegans as a genetic system for dissection of the underlying mechanisms.
微小RNA（miRNA）通过一种定义尚不明确的反义机制抑制靶基因。无细胞和基于细胞的实验支持了miRNA通过阻断翻译起始来抑制其靶mRNA的观点，而在动物模型中的研究则反对这种可能性。我们研究了let-7 miRNA的内源性靶标，它是干细胞命运的重要调节因子。我们报告称，let-7在秀丽隐杆线虫中抑制翻译起始，首次在生物体中证明了这种作用模式。出乎意料的是，尽管之前报道lin-4 miRNA在翻译起始的下游步骤抑制其靶标，但我们也观察到该miRNA对翻译起始的抑制作用。这种抑制机制经常但并非总是与转录本降解同时发生，需要GW182蛋白AIN-1和AIN-2，并作用于不同miRNA靶向的几种mRNA。因此，我们对一组扩展的内源性miRNA靶标的分析表明，在生理条件下翻译起始受到广泛抑制，并将秀丽隐杆线虫确立为剖析潜在机制的遗传系统。
