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

Abstract

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.

The developmentally-timed decay of an essential microRNA family is seed sequence-dependent

“…We and others previously observed slight increases in the prevalence of tailed and trimmed miRNAs as miRNAs approach decay (Baccarini et al, 2011; Kingston and Bartel, 2019; Vieux et al, 2021). In TDMD, miRNAs often experience very high levels of tailing and/or trimming (generally ≥20-40% tailed or trimmed isoforms) (Ameres et al, 2010; Baccarini et al, 2011; Bitetti et al, 2018; Cazalla et al, 2010; Ghini et al, 2018; Kleaveland et al, 2018; Li et al, 2021; Marcinowski et al, 2012). We hypothesized that the prevalence of tailed isoforms might increase at the embryo to L1 transition as the mir-35 family members undergo decay.…”

The developmentally timed decay of an essential microRNA family is seed-sequence dependent

“…We and others previously observed slight increases in tailed and trimmed miRNAs as miRNAs approach decay (Baccarini et al, 2011;Kingston and Bartel, 2019;Vieux et al, 2021). In TDMD, miRNAs often experience very high levels of tailing and/or trimming (generally R20%-40% tailed or trimmed isoforms) (Ameres et al, 2010;Baccarini et al, 2011;Bitetti et al, 2018;Cazalla et al, 2010;Ghini et al, 2018;Kleaveland et al, 2018;Li et al, 2021;Marcinowski et al, 2012). We hypothesized that the prevalence of tailed isoforms might increase at EtoL1 as the mir-35 family members undergo decay.…”

Allosteric regulation of noncoding RNA function by microRNAs

“…Functional interactions between miRNAs and other classes of ncRNAs, including circular RNAs (circRNAs) and long ncRNAs (lncRNAs), have been documented ( 14 , 33 , 36–43 ). However, in most cases these interactions result in the reduction of miRNA abundance by TDMD or inhibition of miRNA activity by sequestration.…”

“…This kind of miRNA:target interaction results in the degradation of the miRNA by a process termed target RNA-directed miRNA degradation (TDMD) ( 13 ). The HSUR1:miR-27 interaction provided the first example of TDMD ( 8 ), a mechanism that is widely employed to regulate miRNA populations ( 14 , 15 ). Diminished abundance of miR-27 promotes the activation of the infected T cell and viral latency ( 16 ).…”