A Truncated Form of Dicer Tilts the Balance of RNA Interference Pathways

•C. elegans DCR-1 is cleaved to produce a stable, abundant C-terminal product•This cleaved product, sDCR-1, enhances the exoRNAi pathway•sDCR-1 inhibits the biogenesis of miRNAs by competing for ALG-1 and ALG-2•sDCR-1 causes the exoRNAi pathway to compete with miRNA biogenesis

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide