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

Here, Li et al. systematically analyzed Argonaute-CLASH (cross-linking, ligation, and sequencing of miRNA-target RNA hybrids) data and identified numerous candidate target RNA-directed miRNA degradation (TDMD) triggers, focusing on their ability to induce nontemplated nucleotide addition at the miRNA 3 ' end. They uncovered widespread TDMD triggers in target RNAs and demonstrated that they could functionally cooperate with 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 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 BCL2L11, 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.

Automated summary

Li et al. systematically analyzed Argonaute-CLASH data to identify candidate target RNA-directed miRNA degradation (TDMD) triggers that induce nontemplated nucleotide addition at the miRNA 3' end. They found widespread TDMD triggers in target RNAs that can cooperate with encoded proteins to induce miRNA degradation.