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Deadenylation: enzymes, regulation, and functional implications

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Lengths of the eukaryotic messenger RNA (mRNA) poly(A) tails are dynamically changed by the opposing effects of poly(A) polymerases and deadenylases. Modulating poly(A) tail length provides a highly regulated means to control almost every stage of mRNA lifecycle including transcription, processing, quality control, transport, translation, silence, and decay. The existence of diverse deadenylases with distinct properties highlights the importance of regulating poly(A) tail length in cellular functions. The deadenylation activity can be modulated by subcellular locations of the deadenylases, cis‐acting elements in the target mRNAs, trans‐acting RNA‐binding proteins, posttranslational modifications of deadenylase and associated factors, as well as transcriptional and posttranscriptional regulation of the deadenylase genes. Among these regulators, the physiological functions of deadenylases are largely dependent on the interactions with the trans‐acting RNA‐binding proteins, which recruit deadenylases to the target mRNAs. The task of these RNA‐binding proteins is to find and mark the target mRNAs based on their sequence features. Regulation of the regulators can switch on or switch off deadenylation and thereby destabilize or stabilize the targeted mRNAs, respectively. The distinct domain compositions and cofactors provide various deadenylases the structural basis for the recruitments by distinct RNA‐binding protein subsets to meet dissimilar cellular demands. The diverse deadenylases, the numerous types of regulators, and the reversible posttranslational modifications together make up a complicated network to precisely regulate intracellular mRNA homeostasis. This review will focus on the diverse regulators of various deadenylases and will discuss their functional implications, remaining problems, and future challenges. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability

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The number of active transcripts for translation is dependent on various kinetic processes during messenger RNA (mRNA) turnover ranging from transcription to degradation. The schematic diagram briefly summarizes the key rate‐limiting processes during eukaryotic mRNA turnover. The transcript number is determined by the rates of mature mRNA production (k1, k2, and k3) and degradation/repression (k4, k5, k6, and k7). Every step may involve various enzymes with dissimilar catalytic properties, which diversify the means of regulation. In the message flow process, the length of mRNA 3′‐end poly(A) tail is one of the key determinants of mRNA stability. The poly(A) length is dynamically regulated by poly(A) polymerases and deadenylases both in the nucleus and in the cytoplasm (k+A, k−A, k+A, and k−A). Active transcripts can be removed either through complete digestion by ribonucleases or through reversible conversion to translationally repressed states such as storage in the stress granules. The quality control of aberrant mRNAs and the feedback regulation are not included in the diagram.
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Structural models of recruiting the CCR4–NOT complex to messenger RNA (mRNA) poly(A) tails by regulators. (a) Recruitment of the CCR4–NOT complex to an ARE (AU‐rich element)‐containing mRNA by an ARE‐BP (ARE‐binding protein), tristetraprolin (TTP). The model is built using the crystal structures of CNOT1p154‐753 (PDB ID: 4B8B), TTP314‐325hCNOT1820‐999 (PDB ID: 4J8S), CNOT1p1088‐1312CAF1p–CCR4p (PDB ID: 4B8C), and CNOT1p1541‐2093CNOT2p–CNOT5p298‐560 (PDB ID: 4B8C). CNOT1p, CNOT2p, CNOT3p, CNOT4p, CNOT5p, CAF1p, CCR4p, CNOT10p, and CNOT11p are yeast proteins, while hCNOT1 and TTP are human proteins. CNOT1p571‐746 corresponds to hCNOT1800‐999, and thus the orientation of CNOT1p154‐753 is determined by aligning the crystal structures of CNOT1p154‐753 (brown) and hCNOT1820‐999 (pink). The organization of the modules is built using the information from previous biophysical, crystal structure, and electron microscopy studies. (b) Scheme of mRNA deadenylation directed by PABP‐dependent binding of the TOB–CCR4–NOT complex. The model is drawn using the crystal structures of CNOT1p1088‐1312CAF1p–CCR4p (PDB ID: 4B8C) and hCAF1a–TOB (PDB ID: 2D5R). The model is obtained by aligning the structures of CAF1p (green) and hCAF1a (purple) in the two complexes.
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The ‘switch on–switch off’ mechanism to promote or inhibit deadenylation in response to cellular signaling. The forward pathway switches on deadenylation to destabilize the stable messenger RNA (mRNA), whereas the reverse pathway switches off deadenylation to stabilize the unstable mRNA. The on and off is triggered by the regulation of the regulator, which is indicated by the color change of the trans‐acting factor.
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Regulation of deadenylase functions by cis‐acting elements and trans‐acting binding proteins. The scheme only shows the typical but not all the identified regulators. The interplays between regulators and the effects of posttranslational modifications are also omitted. The arrows indicate that there are experimental evidences of direct physical interactions to activate deadenylation, while the stop symbols represent that deadenylation is retarded either by exclusion from the target messenger RNA (mRNA) or inhibition of deadenylase activity by the binding partners via physical interactions. For clarity, the references for the pathways are given in the main text. The inhibition factors are shown at the upper side, while the deadenylation‐promoting factors appear at the bottom side of the schematic mRNA. It is noteworthy that although there are evidences for the physical interactions indicated by the arrows, it has not yet been proven for the networks formed by a group of arrows. Abbreviations: CBC, cap‐binding protein complex; eIFs, eukaryotic translation initiation factors; UNR, cold shock domain‐containing protein/upstream of N‐ras protein; PABP, poly(A)‐binding protein; SRE, SMAUG response element; AGO, Argonaute; GW182, GW repeat‐containing protein of 182 kDa; ARE, AU‐rich element; ARE‐BP, ARE‐binding proteins; GRE, GU‐rich element; GRE‐BP, GRE‐binding proteins; PBE, Pumilio‐binding element; PUF, Pumilio/FBF family proteins; CPE, cytoplasmic polyadenylation element; CPEB, CPE‐binding protein; TOB, TOB/BTG family proteins; PAS, poly(A) signal; CPSF, cleavage and polyadenylation specificity factor protein complex; DSE, GU‐ or U‐rich downstream element; CSTF, cleavage stimulating factor complex; Pbp1, PABP‐binding protein‐1, from left to right, respectively.
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Schematic representation of the primary cellular locations of various human deadenylases. CCR4, CAF1, CAF1z, CCR4d, PAN2, and PARN are nuclear–cytoplasmic shuttling proteins. CCR4, CAF1, PAN2, and NOC mainly exist in cytoplasm, while PDE12 is in the mitochondrion. The full‐length PARN mainly exists in the nucleus and accumulates in the nucleoli and Cajal bodies. A truncated form of PARN with the removal of NLS locates in the cytoplasm. CCR4, CAF1, and PAN2 can be recruited to P‐bodies directed by PAN3 or other binding proteins. The CCR4d–CAF1z complex is concentrated in the Cajal bodies.
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Domain compositions and three‐dimensional structures of typical deadenylases. (a) Schematic representation of the domain compositions of various deadenylases. DEDD or EEP is the nuclease domain. R3H and RRM are RNA‐binding domains, CTD is the C‐terminal domain, and NLS is the nuclear localization signal. WD40 is a protein‐binding domain defined by conserved GH and WD dipeptides separated by 40 residues. UCH‐1 is the UCH‐1/peptidase_C19 domain with potential peptidases activity in deubiquitination to recycle ubiquitin. LRR is the leucine‐rich repeats. (b) Tertiary structures of the DEDD and EEP nuclease domains from PARN (left, PDB ID: 2A1R) and CCR4b/CNOT6L (right, PDB ID: 3NGO). The substrate is shown as sticks. (c) Domain/subunit organizations of PARN (left) and CCR4–NOT complex (right). The modeled structure of PARN is obtained by aligning the nuclease domain of two crystal structures composing either the nuclease and R3H domains (PDB ID: 2A1S) or the nuclease and RRM domains (PDB ID: 3D45). PARN is a dimer with subunit binding interfaces formed by the nuclease domain and potential sites in the other domains. The crystal structure of CNOT1–CAF1–CCR4 complex (PDB ID: 4B8C) shows that CCR4 is recruited to CNOT1 via CAF1 through the LLR domain, and the nuclease domains of CCR4 and CAF1 are spatially apart from each other.
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