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RNA uridylation: a key posttranscriptional modification shaping the coding and noncoding transcriptome

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RNA uridylation is a potent and widespread posttranscriptional regulator of gene expression. RNA uridylation has been detected in a range of eukaryotes including trypanosomes, animals, plants, and fungi, but with the noticeable exception of budding yeast. Virtually all classes of eukaryotic RNAs can be uridylated and uridylation can also tag viral RNAs. The untemplated addition of a few uridines at the 3′ end of a transcript can have a decisive impact on RNA’s fate. In rare instances, uridylation is an intrinsic step in the maturation of noncoding RNAs like for the U6 spliceosomal RNA or mitochondrial guide RNAs in trypanosomes. Uridylation can also switch specific miRNA precursors from a degradative to a processing mode. This switch depends on the number of uridines added which is regulated by the cellular context. Yet, the typical consequence of uridylation on mature noncoding RNAs or their precursors is to accelerate decay. Importantly, mRNAs are also tagged by uridylation. In fact, the advent of novel high throughput sequencing protocols has recently revealed the pervasiveness of mRNA uridylation, from plants to humans. As for noncoding RNAs, the main function to date for mRNA uridylation is to promote degradation. Yet, additional roles begin to be ascribed to U‐tailing such as the control of mRNA deadenylation, translation control and possibly storage. All these new findings illustrate that we are just beginning to appreciate the diversity of roles played by RNA uridylation and its full temporal and spatial implication in regulating gene expression.

Dual role of uridylation in let‐7 miRNA maturation. Group I pre‐let‐7 miRNAs end with a 2 nt 3′ overhang and are further processed by Dicer to generate mature let‐7 which downregulate oncogenes in differentiated cells. Group II pre‐let‐7 miRNAs end with a 1 nt 3′ overhang and are mono‐uridylated by TUT4/7 and Gld2 (or possibly mono‐adenylated by Gld2). This single nt addition on the 3′ end restores full Dicer competence to produce let‐7 miRNAs. In embryonic stem cells and many cancers, the RNA binding Lin28A (and possibly Lin28B) binds pre‐let‐7 and, together with the E3 ligase Trim25, recruits TUT4/7 to oligo‐uridylate pre‐let‐7 leading to its degradation by Dis3L2. Prevention of mature let‐7 production induces pluripotency, cell reprogramming, and cancers.
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Uridylation is critical for U6 snRNA maturation. U6 snRNAs are transcribed by polymerase III (Pol III) which terminates transcription by a stretch of four encoded uridines (1) that are immediately bound by the La protein (2). U6 snRNAs are then uridylated by U6 TUTase (TUT1) (3) which favors nibbling by the exoribonuclease Usb1 (4). Usb1 is a phosphodiesterase and generates terminal 2′, 3′ cyclic phosphate. The particular 3′ end formed by four encoded uridines and one exogenous uridine with a terminal 2′, 3′ cyclic phosphate facilitates the recruitment of the LSm2‐8 complex that prevents degradation by the exosome (5).
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Uridylation and guide RNA (gRNA) maturation in trypanosome mitochondria. gRNAs are processed through a sequential maturation process by the mitochondrial 3′ processome (MPsome), containing the TUTase RET1 in complex with the 3′→5' exoribonuclease DSS1. (1) gRNAs are generated by bidirectional transcription of minicircles. The sense and antisense gRNA precursors have complementary regions in the 5′ end and form a duplex. After recruitment of the MPsome (2), the precursors undergo a first uridylation step by RET1 (3), leading to the degradation of the precursors by DSS1 (4). Progression of the MPsome is impeded 10–12 nt from the paired region and a second uridylation step by RET1 occurs (5). After antisense gRNA degradation, mature uridylated gRNAs are incorporated into the gRNA‐binding complex to direct the editosome to editing sites.
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Domain architectures of TUTases are diverse across organisms. Tb, Trypanosoma brucei; Sp, Schizosaccharomyces pombe; Hs, Homo sapiens; An, Aspergillus nidulans; At, Arabidopsis thaliana; Cr, Chlamydomonas reinhardtii; Xt, Xenopus tropicalis; Ce, Caenorhabditis elegans; Dm, Drosophila melanogaster. RRM, RNA recognition motif; PRR, proline‐rich region; KA‐1, kinase‐associated‐1; NLS, nuclear localization signal; DUF, domain of unknown function. Intrinsically disordered regions (IDR) have been predicted using DISOPRED.
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Recycling of RNA‐induced silencing complex (RISC) by RICE1/2. MicroRNA is incorporated into the RISC for target recognition. Perfect pairing of plant miRNA with its target supports slicing of the mRNA by the Argonaute protein. This cleavage results in two pieces, known as the 5′ and 3′ RISC‐cleaved fragments, that will undergo different decay processes. The 3′ RISC‐cleaved fragment is targeted by the 5′→3′ exoribonuclease XRN4. The 5′ RISC‐cleaved fragment is uridylated by HESO1 and the degradation is initiated by RICE1/2. Clearance of the 5′ RISC‐cleaved fragment is ensured by XRN4 and the exosome.
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Uridylation plays diverse roles in mRNA metabolism. Uridylation usually occurs after a deadenylation step. (a) The conserved effect of mRNA uridylation is to trigger degradation in eukaryotes. Recognition of uridylated oligoadenylated mRNAs by the LSm1‐7 complex induces decapping and subsequent 5′→3′ degradation by XRN1. Alternatively, uridylated mRNAs are degraded from their 3′ end by Dis3L2 or the exosome. (b) In Arabidopsis, uridylation prevents excessive deadenylation of mRNAs by restoring an extension of suficient length to allow for PABP binding. (c) Uridylation can also inhibit translation in Xenopus (X. laevis) and starish (Asterina pectinifera) oocytes or activate translation of mitochondrial mRNAs in trypanosomes. (d) Uridylation could also be involved in mRNA storage in starfish oocytes.
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Uridylation induces the degradation of various noncoding RNAs. A few examples were selected to illustrate the destabilizing role of uridylation on noncoding RNAs. (a) Methylation of small RNAs in Arabidopsis preventing uridylation by HESO1. SDN1/2 3′→5′ exoribonucleases trim small RNAs, thereby removing the terminal methylated nucleotide. After trimming by SDN1/2, HESO1 can proceed and uridylate small RNAs that are subsequently degraded by a yet unknown ribonuclease. (b) Uridylation of siRNAs by CDE‐1 in C. elegans. (c) Uridylation of all classes of sRNAs by Cid16 in S. pombe. (d) Target RNA‐directed miRNA degradation (TDMD) of miR‐27 in mammalian cells expressing the mouse cytomegalovirus (MCMV) m169 transcript or in MCMV‐infected murine cells. (e) Uridylation marks a plethora of structured and misprocessed noncoding transcripts produced by Pol I, Pol II, and Pol III to target them to cytosolic destruction by the 3′→5′ exoribonuclease Dis3L2. TSSas, transcription start site‐associated short RNAs.
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Uridylation restricts mirtron accumulation. Left panel: (1) The conventional processing of animal miRNAs starts with the cleavage of the pri‐miRNA by the nuclear Drosha/DGCR8 complex. (2) The generated pre‐miRNA hairpin is then further processed by Dicer/TRBP in the cytoplasm. (3) The resulting miRNA:miRNA* duplex is loaded into Argonaute where the mature miRNA is retained, forming the RISC complex. Right panel: As compared to classical processing for animal miRNAs, mirtrons do not rely on Drosha but instead on the splicing (1) and lariat‐debranching (2) machinery to generate mirtron hairpins ending with AG. Those hairpins are preferential substrates of the TUTase Tailor, which has a better affinity for substrates ending with a G (3). Tailor together with Dis3L2 forms the TRUMP complex in Drosophila. Uridylation by Tailor promotes degradation by Dis3L2, impeding Dicer processing and preventing the formation of mirtrons (4).
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