Target RNAs Strike Back on MicroRNAs

Abstract

MicroRNAs are extensively studied regulatory non-coding small RNAs that silence animal genes throughout most biological processes, typically doing so by binding to partially complementary sequences within target RNAs. A plethora of studies has described detailed mechanisms for microRNA biogenesis and function, as well as their temporal and spatial regulation during development. By inducing translational repression and/or degradation of their target RNAs, microRNAs can contribute to achieve highly specific cell- or tissue-specific gene expression, while their aberrant expression can lead to disease. Yet an unresolved aspect of microRNA biology is how such small RNA molecules are themselves cleared from the cell, especially under circumstances where fast microRNA turnover or specific degradation of individual microRNAs is required. In recent years, it was unexpectedly found that binding of specific target RNAs to microRNAs with extensive complementarity can reverse the outcome, triggering degradation of the bound microRNAs. This emerging pathway, named TDMD for Target RNA-Directed MicroRNA Degradation, leads to microRNA 3′-end tailing by the addition of A/U non-templated nucleotides, trimming or shortening from the 3′ end, and highly specific microRNA loss, providing a new layer of microRNA regulation. Originally described in flies and known to be triggered by viral RNAs, novel endogenous instances of TDMD have been uncovered and are now starting to be understood. Here, we review our current knowledge of this pathway and its potential role in the control and diversification of microRNA expression patterns.

Beyond the seed: structural basis for supplementary microRNA targeting

“…This mechanism may explain why the mammalian Argonautes have evolved away from slicing as the predominant form of target silencing and, moreover, would ensure that the protein does not employ its endonucleolytic activity spuriously. Notably, the crystalized target RNA used here did not contain pairing to the miRNA 3' tail region (g17-g21), which is important for specific miRNA-target interactions in vivo (Broughton, Lovci et al, 2016a) and the process of target directed miRNA degradation (TDMD) (Fuchs Wightman, Giono et al, 2018). Biochemical data also indicate Ago2 is generally capable of using the 3' tail for target recognition (McGeary, Lin et al, 2018).…”

Poly(A)-specific ribonuclease sculpts the 3′ ends of microRNAs

“…7B), PARN may be the culprit enzyme that destructs free miRNAs released from AGO proteins or destabilizes AGO-bound miRNAs in this context. It will be of interest to investigate the role of PARN in a larger paradigm of target RNA-directed miRNA degradation (TDMD), in which the 3 ′ region of miRNAs plays a key role in specifying and eliciting regulatory effects (Fuchs Wightman et al 2018). Finally, we point out that PARN-mediated 3 ′ trimming may influence the recently discovered length-related functions of miRNAs (Yamane et al 2017;Yu et al 2017).…”

Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation

“…88 The unexpected observation that binding of transfected synthetic antisense RNAs with extensive complementarity to miRNAs (miRNA "sponges") led to specific degradation of the targeted miRNA was key to support and further exploration of a miRNA catabolic pathway that has been coined TDMD (Target RNA-Directed MicroRNA Degradation). 89,90 Because human and, in general, metazoan genomes seem to lack highly complementary miRNA binding sites that would trigger cellular TDMD, its physiological relevance remained into question until recently. After the identification of miR-29b as the only member of the miR-29 family associated with TDMD in the cerebellum of zebrafish by the presence of endogenous libra lnc-RNA, or in mice by expression of the homolog Nrep transcript encoding a small protein, 91 additional TDMD examples have been described.…”

“…92 It is also possible that RNA editing mechanisms account for increases in overall complementarity between miRNAs and other cellular RNAs leading to TDMD. 92,93 A recent review by Wightman et al 90 describes the current status of this emerging regulatory pathway of miRNA turnover.…”