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Mechanisms of deadenylation‐dependent decay

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Abstract Degradation of messenger RNAs (mRNAs) plays an essential role in modulation of gene expression and in quality control of mRNA biogenesis. Nearly all major mRNA decay pathways characterized thus far in eukaryotes are initiated by deadenylation, i.e., shortening of the mRNA 3′ poly(A) tail. Deadenylation is often a rate‐limiting step for mRNA degradation and translational silencing, making it an important control point for both processes. In this review, we discuss the fundamental principles that govern mRNA deadenylation in eukaryotes. We use several major mRNA decay pathways in mammalian cells to illustrate mechanisms and regulation of deadenylation‐dependent mRNA decay, including decay directed by adenine/uridine‐rich elements (AREs) in the 3′‐untranslated region (UTR), the rapid decay mediated by destabilizing elements in protein‐coding regions, the surveillance mechanism that detects and degrades nonsense‐containing mRNA [i.e., nonsense‐mediated decay (NMD)], the decay directed by miRNAs, and the default decay pathway for stable messages. Mammalian mRNA deadenylation involves two consecutive phases mediated by the PAN2–PAN3 and the CCR4–CAF1 complexes, respectively. Decapping takes place after deadenylation and may serve as a backup mechanism to trigger mRNA decay if initial deadenylation is compromised. In addition, we discuss how deadenylation impacts the dynamics of RNA processing bodies (P‐bodies), where nontranslatable mRNAs can be degraded or stored. Possible models for mechanisms of various deadenylation‐dependent mRNA decay pathways are also discussed. WIREs RNA 2011 2 167–183 DOI: 10.1002/wrna.40 This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability

A model for translationally coupled deadenylation mediated by the c‐fos major coding‐region determinant (mCRD) of instability. Prior to translation (a), UNR, other auxiliary factors (shown here as a golden yellow circle), and Ccr4 form a bridging complex that brings the 3 poly(A) tail and the mCRD together. Ccr4 access to the poly(A) tail is blocked. Following translation initiation (b), ribosome transit knocks off the bridging complex and somehow activates Ccr4 for accelerated deadenylation.

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Schematic diagram showing a model for default deadenylation (a) and for accelerated deadenylation by nonsense codon (b) in mammalian cells. –P: modification of termination complex, e.g., phosphorylation. EJC: exon–exon junction complex.

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(a) Schematic diagram showing the consecutive phases of deadenylation and mechanistic steps following deadenylation in mammalian cells. (b) Northern blot showing that biphasic deadenylation precedes decay of the RNA body. Transient transcription of β‐globin carrying the c‐fos adenine/uridine‐rich element (ARE) is driven by the Tet promoter. Times indicate hours after transcriptional pulsing of the gene. A: poly(A) messenger RNA (mRNA) as a size marker; ctrl: control mRNA constitutively expressed used as an internal control.

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Schematic diagram illustrating cis‐acting elements or mutations in mammalian messenger RNA (mRNA) that promote accelerated deadenylation.

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Schematic diagram showing eukarytoic messenger RNA (mRNA) decay pathways in the cytoplasm. Thick arrows indicate the major pathway for cytoplasmic mRNA degradation triggered by deadenylation. Thin arrows indicate other steps or pathways. Note that the decay pathway triggered by an endonucleolytic cleavage [e.g., small interfering RNA (siRNA)‐mediated decay] is not depicted here.

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The transcriptional pulsing approach to determine messenger RNA (mRNA) deadenylation and decay kinetics. (a) Schematic diagram illustrating how an inducible promoter can be used to achieve a short burst of mRNA production for kinetic studies. (b) Northern blots showing default deadenylation exhibited by the stable β‐globin mRNA. Transient transcription is driven by either the c‐fos promoter (left) or the Tet promoter (right). Times indicate hours (h) after transcriptional pulsing of β‐globin gene. A: poly(A) mRNA as a size marker; ctrl: control mRNA constitutively expressed used as an internal control.

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The deadenylation rate of a messenger RNA (mRNA) in mammalian cells is determined by interplays among several key players.

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Schematic diagram showing possible modes of accelerated deadenylation promoted by adenine/uridine‐rich elements (AREs) or microRNA (miRNA) binding sites in mammalian cells, which involve either direct recruitment of Ccr4–Caf1 and/or disruption of eIF4F–PABP interaction to open up the closed loop formed between the 5 cap and 3 poly(A) tail. Note that these two mechanisms are not mutually exclusive.

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