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Biogenesis, characterization, and functions of mirtrons

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Abstract MicroRNAs (miRNAs) are major post‐transcriptional regulators of gene expression. They base pair with the complementary target mRNA at the 3′UTR and modulate cellular processes by repressing the mRNA translation or degrading the mRNA. There are well‐documented mechanisms of biogenesis of miRNA; however, a sizeable number of miRNAs are also produced by non‐canonical pathways. Mirtrons represent a predominant class of non‐canonical miRNAs. Mirtrons originate from intronic regions and are produced in a splicing‐dependent and Drosha‐independent manner. Mirtrons constitute about 15% of all miRNAs produced in a human body and have caught attention of researchers worldwide due to their unconventional origin, sequence characteristics, evolutionary dynamics, ability to regulate variety of cellular processes and their immense potential in disease therapeutics. In this comprehensive review we collate the research done in the past decade including biogenesis, sequence characteristics, regulation, and emerging therapeutic roles of mirtrons. This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action
Biogenesis of canonical miRNA and mirtron. (a) Canonical miRNA pathway: The pri‐miRNAs are cleaved by Drosha to form pre‐miRNA. (b) 5′ tailed mirtron pathway: The pri‐miRNA is spliced and debranching is facilitated by a debranching enzyme (Ldbr). The 5′ tail is degraded by a nuclease (yet to be identified) thereby forming pre‐miRNA. (c) Canonical mirtron pathway: Pri‐miRNAs undergo splicing followed by debranching (d) 3′ tailed mirtron pathway: Pri‐miRNAs undergo splicing followed by debranching. The 3′ tail is degraded by an exosome thereby resulting in the formation of pre‐miRNAs. Pre‐miRNAs are then exported from the nucleus to the cytoplasm by Exportin‐5, further processed by dicer and bind to Argonaute proteins. The guide strand is loaded to the RISC complex while the passenger strand is degraded. The miRNA–RISC complex then binds to the target gene suppresses its expression
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Regulation of mirtrons: In Drosophila melanogaster, an exonuclease TUTase called “Tailor” preferentially recognizes AG at the 3′ end of the pre‐miRNAs and selectively adds a poly‐U tail to them. This polyuridylation inhibits recognition by Dicer resulting in degradation of these hairpins by exonucleases. Polyuridylation is more common among mirtrons owing to the presence of splice acceptor site (AG) in mirtrons. On the other hand, majority of the conserved pre‐miRNAs typically do not contain 3′G nucleotide, thus, they escape the tailor recognition and are processed resulting in the formation of mature miRNAs. Newly emerged canonical miRNA hairpins may also possess 3′AG making them susceptible to tailor polyuridylation. The canonical miRNAs ending with UG/GG/CG are relatively less susceptible to tailor polyuridylation and are thus processed via the canonical miRNA biogenesis pathway to form mature miRNAs
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Artificial mirtron mimic RNAi and gene replacement therapy in repeat expansion diseases: Administration of a shRNA comprising of a tailed mirtron sequence as an intron in the replacement gene with a silent mutation (indicated with an asterisk “*”) capable of retaining the function and is also resistant to mirtron RNAi mechanism. The mature miRNA formed from the cellular processing of artificial mirtron binds to the repeated expansion sequence and represses the target mRNA responsible for the disease. In addition, appropriate splicing leads to transcription of the replacement gene (indicated with an asterisk “*”) which results in functional gene replacement resistant to RNAi. In this method, the combination of artificial mirtron along with replacement therapy that is resistant to RNAi from a single vector ensures that the knockdown (of the repeat expansion) and the replacement of the functional gene occur in the same cells; thus minimizing off‐target effects
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Regulatory roles of mirtrons: The mature miRNAs generated by the mirtrons regulate a number of biological processes. Expression of miR‐1017, a tailed mirtron, originating from the neural‐specific acetylcholine receptor directly represses yan, thereby promoting neurogenesis. Expression of miR‐702 in mice represses apoptosis by binding to the apoptotic factor ATF‐6. Expression of miR‐1010 in Drosophila acts like a switch in maintaining nAcRβ2‐mediated neural activity. The feedforward loop of nAcRβ2 activates SKIP and miR‐1010 which suppresses the synaptic potential while the miR‐1010 in turn forms a negative feedback loop and suppresses the nAcRβ2 expression in order to maintain homeostasis. Induced by notch pathway, the expression of miR‐708 represses Tensin3 which inhibits FAK activation and antagonizes cell migration thereby maintaining quiescence. Expression of miR‐1224 represses the anti‐angiogenesis factor called epsin2 leading to primary endothelial cell tube formation and promoting angiogenesis
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Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action
Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs
RNA Processing > Processing of Small RNAs

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