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Review
. 2023 Jan;48(1):26-39.
doi: 10.1016/j.tibs.2022.06.005. Epub 2022 Jul 7.

MicroRNA turnover: a tale of tailing, trimming, and targets

Jaeil Han  1 , Joshua T Mendell  2
Affiliations
Review

MicroRNA turnover: a tale of tailing, trimming, and targets

Jaeil Han et al. Trends Biochem Sci. 2023 Jan.

Abstract

MicroRNAs (miRNAs) post-transcriptionally repress gene expression by guiding Argonaute (AGO) proteins to target mRNAs. While much is known about the regulation of miRNA biogenesis, miRNA degradation pathways are comparatively poorly understood. Although miRNAs generally exhibit slow turnover, they can be rapidly degraded through regulated mechanisms that act in a context- or sequence-specific manner. Recent work has revealed a particularly important role for specialized target interactions in controlling rates of miRNA degradation. Engagement of these targets is associated with the addition and removal of nucleotides from the 3' ends of miRNAs, a process known as tailing and trimming. Here we review these mechanisms of miRNA modification and turnover, highlighting the contexts in which they impact miRNA stability and discussing important questions that remain unanswered.

Keywords: Argonaute; TDMD; ZSWIM8; degradation; miRNA; tailing and trimming; target-directed miRNA degradation.

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Conflict of interest statement

Declaration of interests J.T.M is a scientific advisor for Ribometrix, Inc. and Circ Bio, Inc.

Figures

Figure 1.
Figure 1.. Structure of human AGO2 bound to a small RNA.
(A) Domain organization of human AGO2. (B) The 5′ and 3′ termini of the small RNA (in black) are buried in the AGO MID and PAZ domains (PDB ID: 4W5N) [10]. Protein structures were rendered by UCSF ChimeraX [109].
Figure 2.
Figure 2.. Mechanisms of global miRNA turnover.
(A) During T-cell activation, AGO proteins are ubiquitylated by an unknown ubiquitin ligase and undergo proteasome-mediated degradation, resulting in global miRNA decay [24]. (B) Poxvirus Vp55 adenylates human miRNAs, leading to their degradation by an unknown nuclease(s) [25]. (C) Wispy adenylates miRNAs during the maternal-to-zygotic transition in Drosophila embryos, leading to global clearance of maternal miRNAs [26]. Figure created with Biorender.com.
Figure 3.
Figure 3.. Degradation of miRNAs in plants.
The 3′ ends of plant miRNAs are 2′-O-methylated by HEN1, which recognizes fully-processed miRNA duplexes through its dsRNA binding domains. This prevents HESO1/URT1-mediated 3′ uridylation and subsequent degradation of miRNAs by an unknown nuclease(s). SDN proteins can remove the 2′-O-methyl group, triggering miRNA uridylation and degradation. Figure created with Biorender.com.
Figure 4.
Figure 4.. AGO adopts distinct conformations when engaged with canonical or TDMD-inducing targets.
(A) When bound to a canonical target via base-pairing of the seed region, the miRNA 3′ end is buried in the PAZ domain of AGO (left panel; PDB: 4W5T) [10]. Interaction with a TDMD-inducing target with extended 3′ complementarity, however, exposes the miRNA 3′ end to solvent, which enables tailing and trimming (right panel; PDB: 6MDZ) [72]. Protein structures were rendered by UCSF ChimeraX [109]. (B) Canonical miRNA-target interactions involve base-pairing of the miRNA seed region with or without additional supplementary pairing [1]. A validated canonical binding site for miR-29b in the 3′ UTR of human COL1A1 is shown [110]. (C) Targets that induce TDMD base pair with the miRNA seed region, display extensive complementarity to the miRNA 3′ end, and have central mismatches. Interaction of miR-29b with a TDMD-inducing site in the 3′ UTR of human NREP is shown [82].
Figure 5.
Figure 5.. Current model of TDMD.
The ZSWIM8 E3 ubiquitin ligase recognizes and ubiquitylates AGO engaged with a TDMD target. Extensive 3′-pairing of the miRNA to the TDMD target exposes the 3′ end of the miRNA, enabling tailing by terminal nucleotidyl transferases. Ubiquitylated AGO is degraded by the proteasome and subsequent release of the miRNA leads to its degradation by unknown cytoplasmic RNases. The target transcript is recycled for another round of TDMD. CUL3: Cullin 3; Ub: Ubiquitin. Figure created with Biorender.com.
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References

    1. Bartel DP (2018) Metazoan microRNAs. Cell 173, 20–51 - PMC - PubMed
    1. Ha M and Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15, 509–524 - PubMed
    1. Jonas S and Izaurralde E (2015) Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 16, 421–433 - PubMed
    1. Kozomara A and Griffiths-Jones S (2014) miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 42, D68–73 - PMC - PubMed
    1. Friedman RC, et al. (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19, 92–105 - PMC - PubMed

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