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

Binding of microRNAs (miRNA) to mRNAs normally results in post-transcriptional repression. 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 (crosslinking, ligation, and sequencing of miRNA-target RNA hybrids) data, and identified numerous candidate TDMD triggers based on their ability to induce non-templated nucleotide addition at the miRNA 3 end. When overexpressed in HEK293T cells, nine highly conserved triggers induce degradation of corresponding miRNAs. Consistent with previous reports, both the TDMD base-pairing and surrounding sequences are important for TDMD. CRISPR knockout of endogenous trigger or ZSWIM8, a ubiquitin ligase essential for TDMD, reduce miRNA degradation. Furthermore, degradation of miR-221 and miR-222 by a trigger in BCL2L11, which encodes an apoptotic protein, enhances apoptosis. Therefore, we uncovered widespread TDMD triggers in target RNAs and demonstrated that they can functionally cooperate with the encoded proteins.