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Mechanisms of endonuclease‐mediated mRNA decay

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Abstract Endonuclease cleavage was one of the first identified mechanisms of mRNA decay but until recently it was thought to play a minor role to the better‐known processes of deadenylation, decapping, and exonuclease‐catalyzed decay. Most of the early examples of endonuclease decay came from studies of a particular mRNA whose turnover changed in response to hormone, cytokine, developmental, or nutritional stimuli. Only a few of these examples of endonuclease‐mediated mRNA decay progressed to the point where the enzyme responsible for the initiating event was identified and studied in detail. The discovery of microRNAs and RISC‐catalyzed endonuclease cleavage followed by the identification of PIN (pilT N‐terminal) domains that impart endonuclease activity to a number of the proteins involved in mRNA decay has led to a resurgence of interest in endonuclease‐mediated mRNA decay. PIN domains show no substrate selectivity and their involvement in a number of decay pathways highlights a recurring theme that the context in which an endonuclease function is a primary factor in determining whether any given mRNA will be targeted for decay by this or the default exonuclease‐mediated decay processes. WIREs RNA 2011 2 582–600 DOI: 10.1002/wrna.78 This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability

Overview of mammalian mRNA decay pathways. (a) The default exonuclease‐mediated decay process begins with shortening of the poly(A) tail by the orchestrated activities of the Ccr4/Pop2/Not complex and Pan2/3, and also by the activity of PARN, but details of the interplay between these are still being discovered. This is followed by the assembly of a complex of decapping activators, removal of the cap by Dcp2 and decay of the body of the mRNA either with 5′→3′ polarity by Xrn1, with 3′→5′ polarity by the exosome, or simultaneously with each of these acting on the same mRNA from both ends.4 (b) Endonuclease‐mediated mRNA decay does not involve prior deadenylation. Instead cleavage occurs within the body of the mRNA (coding sequence or 3′‐UTR), followed by degradation of the downstream fragment by Xrn1 and the upstream fragment by the exosome.

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SMG6 and the mRNA surveillance complex. During splicing a complex of proteins (the exon junction complex or EJC) is deposited 24 nucleotides (nt) upstream of each exon junction. These proteins accompany the newly processed mRNA into the cytoplasm, and one of these, Upf3b, is the entry point for mRNA surveillance. Upf2 binds to Upf3b in the cytoplasm and ribosome stalling at an upstream premature termination codon (PTC) brings Upf1 into this complex. Upf1 is phosphorylated by SMG1, which in turn sets up its binding by SMG6 or SMG7. In the scenario shown on the bottom right this juxtaposes the SMG6 PIN domain with the PTC‐containing mRNA where it binds to the EJC, positioning the endonuclease for cleavage and subsequent degradation of the body of the mRNA by Xrn1 and the exosome. It is not known if this displaces Upf3b from the complex but this seems likely. In the alternative scenario shown on the bottom left binding of SMG7 to phosphorylated Upf1 recruits Dcp2 to remove the cap and the body of the mRNA is degraded from either end by Xrn1 and the exosome. It has yet to be determined which of these pathways is principally involved in NMD, or whether both function to differing degrees depending on context.

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Location of the Zc3h12a‐responsive site in interleukin 6 mRNA. A schematic representation of the IL6 mRNA with the five AU‐rich elements (AREs) within the 3′‐UTR identified with black arrows. None of these are required for Zc3h12a‐mediated endonuclease decay. Instead this is determined by a conserved sequence element upstream of these within the 3′‐UTR (open arrow).

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IRE1α mRNA decay. IRE1α is a kinase and ribonuclease that spans the membrane of the endoplasmic reticulum. The N‐terminal luminal portion binds BIP, the major ER chaperone, and the middle kinase and C‐terminal RNase domains are in the cytoplasm. BIP binds to misfolded proteins that accumulate under conditions of ER stress. This enables formation of dimers and higher order aggregates of IRE1α which in turn activates trans‐autophosphorylation (P) and subsequent activation of RNase activity (shown in green). The IRE1α RNase participates in a novel form of splicing, cleaving out an intron in XPB1 pre‐mRNA, which is subsequently ligated and translated to express a transcription factor whose products include BIP. Activated IRE1α also cleaves within mRNAs for membrane‐bound and secreted proteins that are physically associated with the ER by virtue of a signal sequence in their encoded proteins.

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Polysomal ribonuclease 1 (PMR1) mRNA decay. PMR1 is found primarily in two complexes; Complex I consists of an approximately 680‐kDa mRNP that is bound to polysomes and contains PMR1 and its substrate mRNA. It is here that PMR1 acts to catalyze mRNA decay. To join this complex PMR1 must be phosphorylated by c‐Src, a process that takes place in the approximately 140‐kDa Complex II (black star). c‐Src phosphorylation of PMR1 can be stimulated by EGF. Endonuclease decay requires both the tyrosine phosphorylation of PMR1 and translation of its substrate mRNA. In both of these steps PMR1 is bound to the cytoskeleton‐associated proteins Mena and vasodilator‐stimulated phosphoprotein (VASP), which localize PMR1 at the plasma membrane. PMR1 requires Hsp90 for proper folding and steps that interfere with this, such as the ATP analog geldanamycin (GA) result in improperly folded protein that is degraded by the proteasome.

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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Turnover and Surveillance > Regulation of RNA Stability

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