Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
Cell Rep. 2013 Aug 15;4(3):454-63. doi: 10.1016/j.celrep.2013.07.013. Epub 2013 Aug 8.
The RNase III enzyme Dicer is responsible for key steps in the biogenesis of small RNA species in multiple RNA interference pathways. Here, we show that, in the adult C. elegans soma, half of the total DCR-1 protein is expressed as a truncated, stable C-terminal fragment named small DCR-1 (sDCR-1). sDCR-1 operates independently of full-length DCR-1 in two distinct RNAi pathways; it enhances exogenous RNAi (exoRNAi) and concurrently acts as a negative regulator of microRNA (miRNA) biogenesis. Enhancement of exoRNAi relies on sDCR-1 catalytic activity, whereas impinging on miRNA processing does not. Instead, sDCR-1 competes with pre-miRNA processing by interacting with the miRNA-dedicated Argonautes ALG-1 and ALG-2. Finally, triggering a strong exoRNAi response in the presence of elevated levels of sDCR-1 exacerbates the miRNA processing defect. Our results unveil a surprising role for a truncated form of DCR-1 in the modulation of multiple RNAi activities and in the regulation of mechanistic boundaries between pathways.
RNase III 酶 Dicer 负责多种 RNA 干扰途径中小 RNA 物种生物发生的关键步骤。在这里，我们表明，在成年秀丽隐杆线虫体中，总 DCR-1 蛋白的一半以一种截断的、稳定的 C 端片段的形式表达，称为小 DCR-1（sDCR-1）。sDCR-1 在两个不同的 RNAi 途径中独立于全长 DCR-1 发挥作用；它增强外源性 RNAi（exoRNAi），同时作为 microRNA（miRNA）生物发生的负调节剂。exoRNAi 的增强依赖于 sDCR-1 的催化活性，而对 miRNA 加工没有影响。相反，sDCR-1 通过与 miRNA 专用 Argonautes ALG-1 和 ALG-2 相互作用，与 miRNA 加工竞争。最后，在高水平 sDCR-1 的存在下触发强烈的 exoRNAi 反应会加剧 miRNA 加工缺陷。我们的结果揭示了 DCR-1 截断形式在调节多种 RNAi 活性以及调节途径之间机制边界方面的惊人作用。
