Research Article

Target RNA–Directed Trimming and Tailing of Small Silencing RNAs

Science  18 Jun 2010:
Vol. 328, Issue 5985, pp. 1534-1539
DOI: 10.1126/science.1187058

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Close, But Not Too Close

MicroRNAs (miRNAs) in plants are generally highly complementary to their target RNAs, yet, in most animal miRNAs, only the ∼8-nucleotide “seeds” sequence bases pair fully with the target, with few base pairs between the remainder of the miRNA and target. Plant miRNAs are methylated at their 3′ ends, whereas animals' miRNAs are not. Ameres et al. (p. 1534; see the Perspective by Pasquinelli) noticed that, in fruit flies, miRNAs engineered to have high complementarity to target RNAs were present at reduced levels. These miRNAs were trimmed and uridylated at their 3′ ends, features involved in RNA degradation. Fly small interfering RNAs, all of which are methylated at their 3′ ends, were unaffected, unless the methylating enzyme, Hen1, was mutated. Thus, 3′-methylation may prevent complementarity-driven remodeling and degradation of small RNAs.

Abstract

In Drosophila, microRNAs (miRNAs) typically guide Argonaute1 to repress messenger RNA (mRNA), whereas small interfering RNAs (siRNAs) guide Argonaute2 to destroy viral and transposon RNA. Unlike siRNAs, miRNAs rarely form extensive numbers of base pairs to the mRNAs they regulate. We find that extensive complementarity between a target RNA and an Argonaute1-bound miRNA triggers miRNA tailing and 3′-to-5′ trimming. In flies, Argonaute2-bound small RNAs—but not those bound to Argonaute1—bear a 2′-O-methyl group at their 3′ ends. This modification blocks target-directed small RNA remodeling: In flies lacking Hen1, the enzyme that adds the 2′-O-methyl group, Argonaute2-associated siRNAs are tailed and trimmed. Target complementarity also affects small RNA stability in human cells. These results provide an explanation for the partial complementarity between animal miRNAs and their targets.

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