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Functions and mechanisms of RNA tailing by metazoan terminal nucleotidyltransferases

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Abstract Termini often determine the fate of RNA molecules. In recent years, 3′ ends of almost all classes of RNA species have been shown to acquire nontemplated nucleotides that are added by terminal nucleotidyltransferases (TENTs). The best‐described role of 3′ tailing is the bulk polyadenylation of messenger RNAs in the cell nucleus that is catalyzed by canonical poly(A) polymerases (PAPs). However, many other enzymes that add adenosines, uridines, or even more complex combinations of nucleotides have recently been described. This review focuses on metazoan TENTs, which are either noncanonical PAPs or terminal uridylyltransferases with varying processivity. These enzymes regulate RNA stability and RNA functions and are crucial in early development, gamete production, and somatic tissues. TENTs regulate gene expression at the posttranscriptional level, participate in the maturation of many transcripts, and protect cells against viral invasion and the transposition of repetitive sequences. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition RNA Processing > 3′ End Processing RNA Turnover and Surveillance > Regulation of RNA Stability
(a) A phylogenetic relationship of TENTs from vertebrates, worms, and fruit fly. (b) Schematic representation of terminal nucleotidyltransferases (TENTs) from the human, worm, and fruit fly genomes. Canonical nuclear poly(A) polymerase (PAP) is a highly evolutionarily conserved PAP. It comprises an N‐terminal nucleotidyltransferase (NTase) catalytic domain, a central RNA‐binding domain (RBD), and a C‐terminal domain with a nuclear localization signal (NLS). Catalytic activity relies on the highly conserved aspartate triad ([DE]h[DE]h [DE]h in the NTase domain. All TENTs share similar catalytic domain architecture but lack the RBD. The domain architecture of TENTs is diverse, and all additional domains and regions are indicated for each TENT. The length (aa) of each enzyme is indicated on the right
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Selected uridylation‐dependent processes in humans, worms, and flies. (a) Uridylation‐mediated degradation of polyadenylated mRNAs in humans. After deadenylation, mRNAs with poly(A) tails that are shorter than 25 nt are uridylated by TUT4/7, leading to the recruitment of downstream RNA decay factors. The LSM1‐7 complex first interacts with the U‐tail and promotes mRNA decapping by the DCP1‐2 complex. mRNAs that are devoid of a cap are then degraded by the 5′–3′ exonuclease XRN1. Additionally, mRNA can be degraded by the exosome and/or DIS3L2 exonuclease in the 3′‐5′ direction. (b) Pre‐miRNA let‐7 uridylation by TUT4/7. Following their transcription and initial processing, the precursor miRNA (pre‐miRNA) are exported into the cytoplasm (not shown). In differentiated cells where Lin28 is absent, group II pre‐miRNAs that carry a one‐nucleotide 3′ overhang are monouridylated by TUT4/7, thus enabling further processing by Dicer. In cancer and embryonic stem cells, Lin28 binds both groups of let‐7 pre‐mRNAs and recruits TUT4/7. Dicer cannot process oligouridylated pre‐miRNAs, and they are degraded by the 3′‐5′ exonuclease DIS3L2. (c) Various RNA species that are transcribed by Pol I, Pol II, and Pol III can be targeted to the 3′–5′ exosome and/or DIS3L2 exonuclease degradation in a uridylation‐mediated manner. (d) In Drosophila, the decay of multiple RNAs relies on uridylation by Tailor, which forms a complex with the 3′–5′ exonuclease dmDis3L2 (a so‐called TRUMP complex). The stability of mirtrons is particularly controlled by uridylation. Mirtrons arise during splicing and lariat debranching of introns and carry AG at their 3′ ends. The 3′‐AG is uridylated by Tailor, which inhibits their biogenesis and leads to degradation by dmDis3L2. (e) Antiviral RNA uridylation in worms. Upon infection, Orsay virus RNAs are monouridylated by CDE‐1, which promotes their degradation by the 5′–3′ exonuclease XRN1 and 3′–5′ exonucleases of the exosome
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Maturation of U6 snRNA. Following transcription by Pol III, La protein protects the U6 snRNA precursor by binding the four uridines at the 3′ end. La protein is later replaced by TENT1, which uridylates the U6 snRNA 3′ end. The 3′‐5′ exoribonuclease and phosphodiesterase USB1 removes uridines, leaving only five of them, and a terminal 2′,3′ cyclic phosphate (2′3′ > P). The U6 snRNA is further protected by recruitment of the Lsm2‐8 protein complex. The blue dot at the 5′ end represents the γ‐monomethylguanosine triphosphate (meGTP) cap
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Selected aspects of polyadenylation by GLD‐2, TENT2, and Wispy in worms, frogs, and flies, respectively. (a) Polyadenylation by GLD‐2/GLD‐3 plays an important role in the mitosis‐to‐meiosis decision in the adult worm germline through the stabilization of gld‐1 mRNA, which encodes a repressor of mitosis‐promoting mRNAs. At the same time, GLD‐2/GLD‐3 activates repressed meiosis‐related mRNAs. Both events result in the switch from mitosis to meiosis. (b) In worms, GLD‐2 forms two separate complexes with RNA‐binding proteins. GLD‐2/GLD‐3 specifies spermatogenesis, and GLD‐2/RNP‐8 specifies oogenesis. (c) One of the proposed mechanisms of mRNA reactivation in Xenopus oocytes. In immature Xenopus oocytes, CPE‐containing mRNAs (UUUUUAU motif) are bound by CPEB and form a complex with CPSF, TENT2, PARN, ePABP, and Maskin that prevents assembly of the translation initiation complex and thus keeps mRNAs translationally repressed. Upon hormonal stimulation, CPEB is phosphorylated that leads to substantial rearrangements. PARN dissociates from the complex and allows TENT2 to extend poly(A) tails. As a result, ePABP binds to the newly elongated tails. eIF4G displaces Maskin from eIF4E and promotes formation of the translation initiation complex, initiating the translation of mRNAs. 40S, small subunit of the cytoplasmic ribosome; CPE, cytoplasmic polyadenylation element; CPEB, CPE‐binding protein; CPSF, cleavage and polyadenylation specificity factor; eIF3, eukaryotic initiation factor 3; eIF4, eukaryotic initiation factor 4; ePABP, embryonic poly(A) binding protein; PARN, poly(A)‐specific ribonuclease. (d) In the fruit fly, Wispy is recruited to its target mRNAs via interactions with various RNA‐binding proteins
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Mitochondrial poly(A) RNA polymerase (MTPAP) is the only TENT that acts in mitochondria. (a) MTPAP plays a role in the maturation of mt‐tRNAs through adenylation of the tRNA precursor, which generates a substrate for the addition of CCA and further acetylation. MTPAP also polyadenylates mature mt‐tRNAs, leading to defective translation. In both cases, the deadenylase PDE12 removes excessive adenosines. (b) MTPAP generates a complete UAA stop codon and functional ORFs for mt‐mRNA, for which full termination codons are not encoded in the mitochondrial genome. (c) The effect of polyadenylation on mt‐mRNA stability and turnover may be cofactor‐ and/or transcript‐dependent and is not completely understood. In humans and flies, the leucine‐rich pentatricopeptide‐repeat containing protein (LRPPRC)/stem‐loop‐interacting RNA‐binding protein (SLIRP) complex stimulates the polyadenylation activity of MTPAP and protects mRNA from degradation
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Stabilization of polyadenylated mRNAs. During their lifetime, the mRNA poly(A) tails become gradually shortened through CCR4‐NOT‐mediated deadenylation (center) that later leads to complete mRNA degradation from both ends (not shown). TENT4A/B enhances the stability of mRNAs by the mixed A/G tailing of their poly(A) tails (on the left). The guanosine residues in the terminal positions of poly(A) tails protect mRNA from deadenylation by CCR4‐NOT because CCR4‐NOT is unable to efficiently remove the guanidine residue. Proteins from the TENT5 family elongate mRNA poly(A) tails in the cytoplasm, ultimately extending the mRNA lifespan and enhancing its expression (on the right). Remaining unknown are the ways in which TENT4 and TENT5 ncPAPs recognize their target RNA and whether other protein cofactors facilitate their function
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In the nucleus, polyadenylation by TENT4B/A, acting alone or in complex with other proteins, induces the exosome‐mediated decay of various RNA species (upper panel). TENT4B/A also cooperates with the poly(A)‐specific ribonuclease PARN to promote H/ACA box snoRNA maturation (bottom panel)
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RNA Turnover and Surveillance > Regulation of RNA Stability
RNA Processing > 3′ End Processing
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition

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