Journal
CURRENT BIOLOGY
Volume 21, Issue 22, Pages 1878-1887Publisher
CELL PRESS
DOI: 10.1016/j.cub.2011.09.034
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Funding
- National Institutes of Health [GM62868, GM65236]
- EMBO [ALTF 522-2008]
- Austrian Science Fund (FWF) Erwin Schrodinger-Auslandsstipendium [J2832-B09]
- Austrian Science Fund (FWF) [W1207] Funding Source: Austrian Science Fund (FWF)
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Background: MicroRNAs (miRNAs) are similar to 22 nucleotide (nt) small RNAs that control development, physiology, and pathology in animals and plants. Production of miRNAs involves the sequential processing of primary hairpin-containing RNA polymerase II transcripts by the RNase III enzymes Drosha in the nucleus and Dicer in the cytoplasm. miRNA duplexes then assemble into Argonaute proteins to form the RNA-induced silencing complex (RISC). In mature RISC, a single-stranded miRNA directs the Argonaute protein to bind partially complementary sequences, typically in the 3' untranslated regions of messenger RNAs, repressing their expression. Results: Here, we show that after loading into Argonaute1 (Ago1), more than a quarter of all Drosophila miRNAs undergo 3' end trimming by the 3'-to-5' exoribonuclease Nibbler (CG9247). Depletion of Nibbler by RNA interference (RNAi) reveals that nniRNAs are frequently produced by Dicer-1 as intermediates that are longer than similar to 22 nt. Trimming of miRNA 3' ends occurs after removal of the miRNA* strand from pre-RISC and may be the final step in RISC assembly, ultimately enhancing target messenger RNA repression. In vivo, depletion of Nibbler by RNAi causes developmental defects. Conclusions: We provide a molecular explanation for the previously reported heterogeneity of miRNA 3' ends and propose a model in which Nibbler converts miRNAs into isoforms that are compatible with the preferred length of Ago1-bound small RNAs.
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