The Exoribonuclease Nibbler Controls 3′ End Processing of MicroRNAs in Drosophila

• Published in: Current biology 2011-11, Vol.21 (22), p.1888-1893
• Main Authors: Liu, Nan, Abe, Masashi, Sabin, Leah R., Hendriks, Gert-Jan, Naqvi, Ammar S., Yu, Zhenming, Cherry, Sara, Bonini, Nancy M.
• Format: Article
• Language: English
• Subjects: Animals; Argonaute Proteins - genetics; Argonaute Proteins - metabolism; Blotting, Northern; Cell Line; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Exoribonucleases - metabolism; MicroRNAs - metabolism; Molecular Sequence Data; Polymerase Chain Reaction; RNA Interference; RNA Processing, Post-Transcriptional; RNA, Messenger - metabolism; RNA-Induced Silencing Complex - metabolism; Sequence Analysis, RNA
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2011.10.006

MicroRNAs (miRNAs) are endogenous noncoding small RNAs with important roles in many biological pathways; their generation and activity are under precise regulation [1–3]. Emerging evidence suggests that miRNA pathways are precisely modulated with controls at the level of transcription [4–8], processing [9–11], and stability [12, 13], with miRNA deregulation linked with diseases [14] and neurodegenerative disorders [15]. In the Drosophila miRNA biogenesis pathway, long primary miRNA transcripts undergo sequential cleavage [16–18] to release the embedded miRNAs. Mature miRNAs are then loaded into Argonaute1 (Ago1) within the RNA-induced silencing complex (RISC) [19, 20]. Intriguingly, we found that Drosophila miR-34 displays multiple isoforms that differ at the 3′ end, suggesting a novel biogenesis mechanism involving 3′ end processing. To define the cellular factors responsible, we performed an RNA interference (RNAi) screen and identified a putative 3′→5′ exoribonuclease CG9247/nibbler essential for the generation of the smaller isoforms of miR-34. Nibbler (Nbr) interacts with Ago1 and processes miR-34 within RISC. Deep sequencing analysis revealed a larger set of multi-isoform miRNAs that are controlled by nibbler. These findings suggest that Nbr-mediated 3′ end processing represents a critical step in miRNA maturation that impacts miRNA diversity. ► A new fly gene, nibbler/CG9247 (nbr), is identified in miR-34 3′ end processing ► Nbr forms a protein complex with Ago1, and both are required for trimming ► Nbr-mediated 3′ end processing modulates a large number of miRNAs ► Nbr modulation of the miRNA profile impacts gene expression