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Regulation of microRNA biogenesis and turnover by animals and their viruses - PubMed

Review

Regulation of microRNA biogenesis and turnover by animals and their viruses

Valentina Libri et al. Cell Mol Life Sci. 2013 Oct.

Abstract

MicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes.

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Figures

Fig. 1
Fig. 1

Schematic overview of microRNA biogenesis and regulation in animals. a The canonical biogenesis pathway. Pri-miRNAs are transcribed in the nucleus by polymerase II with a cap (m7G, 7-methylguanosine-cap) and poly A tail. The pri-miRNA can harbour a single pre-miRNA or a cluster of pre-miRNAs; the mature miRNA sequence is depicted in red. Cleavage of the pri-miRNA occurs in the nucleus by the Microprocessor complex, composed minimally of Drosha and DGCR8, which interact with helicases p68 and p72. The pre-miRNA is then exported through the nuclear pore complex into the cytoplasm where the stem is cleaved by Dicer, supported by TRBP or PACT. The miRNA/miRNA* duplex is loaded into the Ago protein within RISC, where one part of the strand is preferentially retained; this complex contains an Ago protein and GW182, which is required for gene silencing. b Regulation of pri-miRNA cleavage. Proteins can either positively (green) or negatively (red) influence cleavage of pri-miRNAs by Drosha, based on direct interactions with the pri-miRNA or interactions with auxiliary proteins p68/p72 (indicated by arrows). Factors depicted in both green and red can behave as positive or negative regulators depending on the identity of the miRNA and the presence of other factors. Mature miRNAs can also regulate pri-miRNA processing through interactions downstream of the stem-loop: let-7 promotes processing of pri-let-7 whereas miR-709 inhibits processing of pri-miR 15/16. c Regulation of pre-miRNA export. Two viral non-coding RNAs inhibit miRNA translocation to the cytoplasm: VA1 competes with endogenous pre-miRNAs for binding to Exportin-5 whereas the viral miRNA, Bmnp-miR-1, regulates export indirectly (dotted line) by targeting RanGTP. d Regulation of pre-miRNA cleavage by Dicer. Proteins that regulate Dicer processing include: (1) Lin28 (Lin28A), which recruits TUT4 that oligo-uridylates pre-miRNAs leading to degradation, (2) MCPIP1 which cleaves the loop, (3) TDP-43 and KSRP, which bind to the loops of both pri-miRNAs and pre-miRNAs and (4) BCDIN3D, which can add methyl groups to the 5′ end of pre-miRNA and inhibit recognition by Dicer. The RNA factors that are known to inhibit Dicer processing include an ~800 non-coding RNA termed rnsc-1, VA RNAs from Vaccinia virus (black) and a viral miRNA that regulates Dicer indirectly (dotted line)

Fig. 2
Fig. 2

RNA motifs that mediate regulation of pri-miRNA or pre-miRNA processing. Proteins that positively (green) or negatively (red) regulate biogenesis associate with specific motifs in the stem-loop structures; depending on localization of the proteins, these either regulate the pri-miRNA or the pre-miRNA as listed below the hairpin; Lin28 and KSRP can regulate both forms. The identity of the miRNAs that contain the recognition motifs and have been validated to be regulated by each protein are listed to the left of the hairpin structure. Binding of miR-709 to pri-miR-15/16 inhibits its processing whereas binding of let-7 to pri-let-7 stimulates its processing

Fig. 3
Fig. 3

Alternative miRNA biogenesis pathways in animals and viruses. a Drosha-independent biogenesis. Pre-miRNAs are co-transcribed with tRNAs in Pol III transcripts in MHV68 and bypass processing by Drosha. Pre-miRNA like miRNAs in HVS are derived from the same Pol II transcripts as HSURs and require the Integrator for generation of their 5′ ends. Cellular miRNAs termed mirtrons also do not require Drosha: they are Pol II transcripts that are excised by splicing and linearized by lariat debranching; tailed mirtrons require further 5′ or 3′ trimming by nucleases and then they are directly processed by Dicer. b Dicer-independent biogenesis. The highly conserved miRNA, miR-451 is produced in a dicer-independent mechanism involving cleavage by Ago. The mature miRNA (red) derives from the stem as well as loop sequence of the pre-miRNA

Fig. 4
Fig. 4

Target-mediated miRNA degradation. Different sources of target RNA can induce miRNA decay including two herpesviral transcripts (Herpesvirus saimiri HSUR1 and murine Cytomegalovirus m169) and transgenic expressed miRNA targets with extensive basepairing. Whether there are endogenous mRNAs that induce miRNA degradation remains to be investigated. Both in vertebrates and invertebrates target-mediated miRNA degradation has been associated with tailing and trimming of miRNAs. The relationship between tailing and trimming is still unclear, and the factors involved in mediating these effects and subsequent degradation remain to be determined

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