mRNA surveillance
mRNA surveillance mechanisms are
Overview
The
mRNA surveillance has been documented in
Three surveillance mechanisms are currently known to function within cells: the nonsense-mediated mRNA decay pathway (NMD); the nonstop mediated mRNA decay pathways (NSD); and the no-go mediated mRNA decay pathway (NGD).
Nonsense-mediated mRNA decay
Overview
Nonsense-mediated decay is involved in detection and decay of mRNA transcripts which contain premature termination codons (PTCs). PTCs can arise in cells through various mechanisms:
A surveillance complex consisting of various proteins (
Seven smg genes (smg1-7) and three UPF genes (Upf1-3) have been identified in Saccharomyces cerevisiae and Caenorhabditis elegans as essential trans-acting factors contributing to NMD activity.[12][13] All of these genes are conserved in Drosophila melanogaster and further mammals where they also play critical roles in NMD. Throughout eukaryotes there are three components which are conserved in the process of NMD.[14] These are the Upf1/SMG-2, Upf2/SMG-3 and Upf3/SMG-4 complexes. Upf1/SMG-2 is a phosphoprotein in multicellular organisms and is thought to contribute to NMD via its phosphorylation activity. However, the exact interactions of the proteins and their roles in NMD are currently disputed.[11][12][14][15][16]
Mechanism in mammals
A premature stop codon must be recognized as different from a normal stop codon so that only the former triggers a NMD response. It has been observed that the ability of a nonsense codon to cause mRNA degradation depends on its relative location to the downstream sequence element and associated proteins.
When the ribosome reaches a PTC the translation factors eRF1 and eRF3 interact with retained EJC complexes though a multiprotein bridge.[21] The interactions of UPF1 with the terminating complex and with UPF2/UPF3 of the retained EJCs are critical. It is these interactions which target the mRNA for rapid decay by endogenous nucleases[18][21]
Mechanism in invertebrates
Studies involving organisms such as
Mechanism in plants
There are two mechanisms of PTC recognition in plants: according to its distance from the EJC (like in vertebrates) or from the poly-A tail. The NMD mechanism in plants induces the decay of mRNAs containing a 3’UTR longer than 300 nucleotides, that is why the proportion of mRNAs with longer 3'UTRs is much lower in plants than in vertebrates.[23][24]
NMD avoidance
mRNAs with nonsense mutations are generally thought to be targeted for decay via the NMD pathways. The presence of this premature stop codon about 50-54 nucleotides 5' to the exon junction appears to be the trigger for rapid decay; however, it has been observed that some mRNA molecules with a premature stop codon are able to avoid detection and decay.[17][25] In general, these mRNA molecules possess the stop codon very early in the reading frame (i.e. the PTC is AUG-proximal). This appears to be a contradiction to the current accepted model of NMD as this position is significantly 5' of the exon-exon junction.[26]
This has been demonstrated in β-globulin. β-globulin mRNAs containing a nonsense mutation early in the first exon of the gene are more stable than NMD sensitive mRNA molecules. The exact mechanism of detection avoidance is currently not known. It has been suggested that the poly-A binding protein (PABP) appears to play a role in this stability.[27] It has been demonstrated in other studies that the presence of this protein near AUG-proximal PTCs appears to promote the stability of these otherwise NMD sensitive mRNAs. It has been observed that this protective effect is not limited only to the β-globulin promoter.[25] This suggests that this NMD avoidance mechanism may be prevalent in other tissue types for a variety of genes. The current model of NMD may need to be revisited upon further studies.
Nonstop mediated mRNA decay
Overview
Nonstop mediated decay (NSD) is involved in the detection and decay of mRNA transcripts which lack a stop codon.[29][30] These mRNA transcripts can arise from many different mechanisms such as premature 3' adenylation or cryptic polyadenylation signals within the coding region of a gene.[31] This lack of a stop codon results a significant issue for cells. Ribosomes translating the mRNA eventually translate into the 3'poly-A tail region of transcripts and stalls. As a result, it cannot eject the mRNA.[32] Ribosomes thus may become sequestered associated with the nonstop mRNA and would not be available to translate other mRNA molecules into proteins. Nonstop mediated decay resolves this problem by both freeing the stalled ribosomes and marking the nonstop mRNA for degradation in the cell by nucleases. Nonstop mediated decay consists of two distinct pathways which likely act in concert to decay nonstop mRNA.[29][30]
Ski7 pathway
This pathway is active when Ski7 protein is available in the cell. The Ski7 protein is thought to bind to the empty A site of the ribosome. This binding allows the ribosome to eject the stuck nonstop mRNA molecule – this even frees the ribosome and allows it to translate other transcripts. The Ski7 is now associated with the nonstop mRNA and it is this association which targets the nonstop mRNA for recognition by the cytosolic exosome. The Ski7-exosome complex rapidly deadenylates the mRNA molecule which allows the exosome to decay the transcript in a 3' to 5' fashion.[29][30]
Non-Ski7 pathway
A second type of NSD has been observed in yeast. In this mechanism, the absence of Ski7 results in the loss of poly-A tail binding PABP proteins by the action of the translation ribosome. The removal of these PABP proteins then results in the loss of the protective 5'm7G cap. The loss of the cap results in rapid degradation of the transcript by an endogenous 5'-3' exonuclease such as XrnI.[30]
No-Go decay
No-Go decay (NGD) is the most recently discovered surveillance mechanism.
Evolution
It is possible to determine the
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