Widespread microRNA degradation elements in target mRNAs can assist the encoded proteins

Binding of microRNAs (miRNAs) to mRNAs normally results in post-transcriptional repression of gene expression. However, extensive base-pairing between miRNAs and target RNAs can trigger miRNA degradation, a phenomenon called target RNA-directed miRNA degradation (TDMD). Here, we systematically analy...

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Bibliographic Details
Published in:Genes & development 2021-12, Vol.35 (23-24), p.1595-1609
Main Authors: Li, Lu, Sheng, Peike, Li, Tianqi, Fields, Christopher J, Hiers, Nicholas M, Wang, Yuzhi, Li, Jianping, Guardia, Casey M, Licht, Jonathan D, Xie, Mingyi
Format: Article
Language:English
Subjects:
Argonaute Proteins - genetics
Argonaute Proteins - metabolism
Base Pairing
MicroRNAs - genetics
MicroRNAs - metabolism
Research Paper
RNA Stability - genetics
RNA, Messenger - genetics
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Summary:Binding of microRNAs (miRNAs) to mRNAs normally results in post-transcriptional repression of gene expression. However, extensive base-pairing between miRNAs and target RNAs can trigger miRNA degradation, a phenomenon called target RNA-directed miRNA degradation (TDMD). Here, we systematically analyzed Argonaute-CLASH (cross-linking, ligation, and sequencing of miRNA-target RNA hybrids) data and identified numerous candidate TDMD triggers, focusing on their ability to induce nontemplated nucleotide addition at the miRNA 3' end. When exogenously expressed in various cell lines, eight triggers induce degradation of corresponding miRNAs. Both the TDMD base-pairing and surrounding sequences are essential for TDMD. CRISPR knockout of endogenous trigger or ZSWIM8, a ubiquitin ligase essential for TDMD, reduced miRNA degradation. Furthermore, degradation of miR-221 and miR-222 by a trigger in , which encodes a proapoptotic protein, enhances apoptosis. Therefore, we uncovered widespread TDMD triggers in target RNAs and demonstrated an example that could functionally cooperate with the encoded protein.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.348874.121