small RNAs tailing
Target RNA-directed destruction of miRNAs in Drosophila
In flies, small interfering RNAs (siRNAs) direct Argonaute2 (Ago2) to defend cells from viruses and transposons. In contrast, micro RNAs (miRNAs) mainly guide Ago1 to repress target mRNAs. A key step in the production of a functional Ago2/siRNA but not an Ago1/miRNA complex is Hen1-mediated methylation of the small RNA guide at the 2* hydroxyl of the 3*-terminal ribose. The function of this modification in animals is unknown. Here we show that highly complementary target RNAs decrease the steady-state level of Ago1-bound miRNAs. In vitro, the decline in miRNA levels requires high, but not complete complementarity between the target RNA and the small RNA; is accompanied by 3*-terminal nucleotide addition; and is blocked by Hen1-catalyzed 2*-O-methylation of small RNAs. The absence of Hen1 results in 3*-terminal uridylation and destabilization of Ago2-associated small RNAs in vivo. Our results suggest that small RNA-target RNA complementarity has shaped the coevolution of miRNAs and their target RNAs in flies and we present human cultured cell experiments that the target RNA-dependent small RNA tailing and degradation machinery may be conserved in mammals.