Aberrant termination triggers nonsense-mediated mRNA decay

Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655-0122, USA.
Biochemical Society Transactions (Impact Factor: 3.24). 03/2006; 34(Pt 1):39-42. DOI: 10.1042/BST20060039
Source: PubMed

ABSTRACT NMD (nonsense-mediated mRNA decay) is a cellular quality-control mechanism in which an otherwise stable mRNA is destabilized by the presence of a premature termination codon. We have defined the set of endogenous NMD substrates, demonstrated that they are available for NMD at every round of translation, and showed that premature termination and normal termination are not equivalent biochemical events. Premature termination is aberrant, and its NMD-stimulating defects can be reversed by the presence of tethered poly(A)-binding protein (Pab1p) or tethered eRF3 (eukaryotic release factor 3) (Sup35p). Thus NMD appears to be triggered by a ribosome's failure to terminate adjacent to a properly configured 3'-UTR (untranslated region), an event that may promote binding of the UPF/NMD factors to stimulate mRNA decapping.

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Available from: stephanie kervestin, Aug 14, 2015
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    • "The nonsense-mediated mRNA decay (NMD) pathway is a specialized pathway that contributes to the recognition and rapid degradation of mRNA with premature termination codons, thus preventing the production of non-functional, potentially harmful, truncated proteins. NMD influences the expression of a number of human genetic diseases by affecting the expression of genes carrying nonsense mutations (reviewed in Culbertson and Leeds, 2003; Amrani et al., 2006; Nicholson et al., 2009) Three core trans-acting factors are required for NMD in all eukaryotes. These are the upframeshift proteins Upf1p, Upf2p and Upf3p. "
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    ABSTRACT: The eukaryotic nonsense-mediated mRNA decay pathway (NMD) is a specialized pathway that contributes to the recognition and rapid degradation of mRNA with premature termination codons. In addition to mRNAs containing premature termination codons, NMD degrades non-nonsense-containing, natural mRNAs. Approximately 5-10% of the total Saccharomyces cerevisiae transcriptome is affected when NMD is inactivated. The regulation of natural mRNAs by NMD has physiological consequences. However, the physiological outcomes associated with the degradation of specific natural mRNAs by NMD are not fully understood. Here, we examined the physiological consequences resulting from the NMD-mediated regulation of an mRNA involved in copper homeostasis, in an attempt to understand why nmd mutant strains are more tolerant of toxic copper levels than wild-type yeast strains. We found that wild-type (UPF1) and upf1Δ mutants accumulate similar amounts of total copper when grown in medium containing elevated levels of copper; however, the copper levels in the cytoplasm of wild-type yeast cells were higher than in the upf1Δ mutant. Copper tolerance by the upf1Δ mutant is dependent on the presence of CTR2. Deletion of CTR2 resulted in similar cytoplasmic copper levels in wild-type and upf1Δ mutant strains, regardless of the environmental copper levels. This suggests that CTR2 plays a role in regulating the level of copper in the cytoplasm. We also found that the upf1Δ mutant contained elevated copper levels in the vacuole relative to wild-type yeast cells, after both strains were exposed to elevated copper levels
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    • "It triggers the rapid degradation of mRNAs with premature termination codons preventing the production of potentially harmful truncated proteins. NMD also regulates the expression of some natural mRNAs as well (reviewed in Culbertson and Leeds 2003; Amrani et al. 2006; Nicholson et al. 2009). Three core trans-acting factors are required for NMD in all eukaryotes. "
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    ABSTRACT: The eukaryotic nonsense-mediated mRNA (NMD) is a specialized pathway that leads to the recognition and rapid degradation of mRNAs with premature termination codons, and importantly some natural mRNAs as well. Natural mRNAs with atypically long 3'-untranslated regions (UTRs) are degraded by NMD in Saccharomyces cerevisiae. A number of S. cerevisiae mRNAs undergo alternative 3'-end processing producing mRNA isoforms that differ in their 3'-UTR lengths. Some of these alternatively 3'-end processed mRNA isoforms have atypically long 3'-UTRs and would be likely targets for NMD-mediated degradation. Here, we investigated the role NMD plays in the regulation of expression of CTR2, which encodes a vacuolar membrane copper transporter. CTR2 pre-mRNA undergoes alternative 3'-end processing to produce two mRNA isoforms with 300-nt and 2-kb 3'-UTRs. We show that both CTR2 mRNA isoforms are differentially regulated by NMD. The regulation of CTR2 mRNA by NMD has physiological consequences, since nmd mutants are more tolerant to toxic levels of copper relative to wild-type yeast cells and the copper tolerance of nmd mutants is dependent on the presence of CTR2.
    Current Genetics 09/2011; 57(6):421-30. DOI:10.1007/s00294-011-0356-0 · 2.68 Impact Factor
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    • "(Figure 2C). The lowered Neurog3 F mRNA level could be a result of its destabilization by the presence of a long 3′-UTR (Amrani et al., 2006). "
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