Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 25, Issue 11, Pages 1019-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41594-018-0136-3
Keywords
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Funding
- Ministry of Science and Technology of China [2017YFA0506400]
- National Natural Science Foundation of China [31670827, 91640115]
- Chinese 111 program [B06018]
- Chinese Academy of Science foundation [22KJZD-EW-L12]
- NIH [HG004659, GM049369, GM052872]
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MicroRNAs (miRNAs) are well known to target 3' untranslated regions (3' UTRs) in mRNAs, thereby silencing gene expression at the post-transcriptional level. Multiple reports have also indicated the ability of miRNAs to target protein-coding sequences (CDS); however, miRNAs have been generally believed to function through similar mechanisms regardless of the locations of their sites of action. Here, we report a class of miRNA-recognition elements (MREs) that function exclusively in CDS regions. Through functional and mechanistic characterization of these 'unusual' MREs, we demonstrate that CDS-targeted miRNAs require extensive base-pairing at the 3' side rather than the 5' seed; cause gene silencing in an Argonaute-dependent but GW182-independent manner; and repress translation by inducing transient ribosome stalling instead of mRNA destabilization. These findings reveal distinct mechanisms and functional consequences of miRNAs that target CDS versus the 3' UTR and suggest that CDS-targeted miRNAs may use a translational quality-control-related mechanism to regulate translation in mammalian cells.
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