An mRNA Surveillance Mechanism That Eliminates Transcripts Lacking Termination Codons

Frischmeyer, Pamela A.; Hoof, Ambro van; O’Donnell, Kathryn A.; Guerrerio, Anthony L.; Parker, Roy; Dietz, Harry C.

doi:10.1126/science.1067338

Cited by 498 publications

(473 citation statements)

References 20 publications

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“…In either case, a simple explanation for this interaction is that [PSI ϩ ] causes readthrough of normal stop codons and any other stop codons in the 3Ј UTR. Such read-through would cause a ribosome to reach the very 3Ј end of the mRNA and would trigger nonstop mRNA decay (22,23). This possibility is supported by the observation that [PSI ϩ ] leads to a Ski7p-dependent reduction in the levels of the PGK1 and ade2-1 mRNAs (Fig.…”

Section: [Psi ؉ ] and Premature Stop Codonssupporting

confidence: 59%

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Genetic interactions between [ PSI ⁺ ] and nonstop mRNA decay affect phenotypic variation

Wilson

Meaux

Parker

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The functions of the eRF3 protein in translation termination and prion propagation are easily separated. The N-terminal domain of eRF3 is required for prion propagation (7,8). Point mutations in, or deletion of, the N-terminal domain disrupt the prion propagation function of yeast eRF3, and the N-terminal domain by itself is sufficient for prion propagation (3,7,9). The translation termination function of eRF3 requires the well conserved C-terminal domain. Deletion of the C-terminal domain is lethal, presumably because of defects in translation termination, and point mutations in the C-terminal domain reduce translation termination efficiency (9). Thus, the prion property of eRF3 is a property of the N-terminal domain, whereas the C-terminal domain is required for translation termination.The ability of eRF3 to exist in [PSI ϩ ] and [psi Ϫ ] states has been conserved during evolution and is present in the eRF3 proteins of several species and genera of yeast (10)(11)(12)(13)(14) ] induces phenotypic variation by suppressing premature stop codons, it has been reported that in seven cases the effect of [PSI ϩ ] was similar to the effect of upf1⌬, which also suppresses premature stop codons (see below) (16). However, it was also reported that in four other cases the effect of [PSI ϩ ] was not mimicked by upf1⌬, suggesting that there may be additional mechanisms by which [PSI ϩ ] affects phenotypes (16).Two lines of evidence suggest that [PSI ϩ ] affects translation termination not only at premature stop codons, but also at wild-type stop codons naturally found at the 3Ј end of coding regions. First, the frequency of extra stop codons just 3Ј of the normal stop codon of yeast genes is higher than expected, suggesting that read-through of the normal stop codons occurs at a frequency that is a significant factor over evolutionary time (19). Second, Namy et al. (20) identified eight genes that had a poor stop codon context. In an artificial reporter gene, translation termination at these stop codon contexts was affected by [PSI ϩ ]. Thus, [PSI ϩ ] might affect phenotypic variation by promoting read-through of normal stop codons (16)(17)(18)20).In addition to PSI directly affecting translation termination of premature and͞or normal stop codons, there may be indirect effects on mRNA stability because translation termination and mRNA stability are intimately linked (16). Two aspects of this link are nonsense-mediated mRNA decay and nonstop mRNA decay. Nonsense-mediated mRNA decay is the process of rapidly degrading mRNAs that contain a premature stop codon (reviewed in ref. 21). It is thought that nonsense-containing mRNAs are recognized as a consequence of premature translation termination. Because [PSI ϩ ] affects the efficiency of translation termination, it may also affect nonsense-mediated mRNA decay. Nonstop mRNA decay is the process of degrading mRNAs that do not contain stop codons (22,23). Nonstop mRNAs are

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Section: [Psi ؉ ] and Premature Stop Codonssupporting

confidence: 59%

“…Because [PSI ϩ ] affects the efficiency of translation termination, it may also affect nonsense-mediated mRNA decay. Nonstop mRNA decay is the process of degrading mRNAs that do not contain stop codons (22,23 …”

mentioning

confidence: 99%

Genetic interactions between [ PSI ⁺ ] and nonstop mRNA decay affect phenotypic variation

Wilson

Meaux

Parker

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…2D), suggesting that sphinx720RW carries a loss-of-function allele, sphinx Ϫ . The absence of sphinx transcripts in the mutant strain is likely to be a consequence of the RNA surveillance system that eliminates any transcripts that are not properly spliced (19)(20)(21) because of the changed splice sites and cryptic splice sites in our engineered sphinx sequence.…”

Section: Evolution Of Genementioning

confidence: 99%

The evolution of courtship behaviors through the origination of a new gene in Drosophila

Dai

Chen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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New genes can originate by the combination of sequences from unrelated genes or their duplicates to form a chimeric structure. These chimeric genes often evolve rapidly, suggesting that they undergo adaptive evolution and may therefore be involved in novel phenotypes. Their functions, however, are rarely known. Here, we describe the phenotypic effects of a chimeric gene, sphinx, that has recently evolved in Drosophila melanogaster. We show that a knockout of this gene leads to increased male-male courtship in D. melanogaster, although it leaves other aspects of mating behavior unchanged. Comparative studies of courtship behavior in other closely related Drosophila species suggest that this mutant phenotype of male-male courtship is the ancestral condition because these related species show much higher levels of male-male courtship than D. melanogaster. D. melanogaster therefore seems to have evolved in its courtship behaviors by the recruitment of a new chimeric gene.chimeric gene ͉ gene duplication ͉ new functions ͉ phenotype evolution C omparative genomic analyses in various eukaryotes often reveal new genes that have evolved throughout the combination of unrelated genes or their duplicates (1-3). These new genes have usually evolved rapidly with a pattern of evolution that was shaped by positive Darwinian selection (4-6), suggesting that these chimeric genes have novel functions. Previous studies of molecular functions in new gene duplicates revealed the origination of important molecular functions in animals (6-8). A new gene becomes fixed in its initial stage in natural populations and subsequently evolves under various evolutionary forces (9). Understanding of this process requires the knowledge of the phenotypic effects of new gene duplicates because such effects are usually the targets of the positive selection that would determine the fate of the new gene duplicates. However, the phenotypes of these new genes are almost never known.In a survey of species-specific genes, we identified a courtship gene, sphinx, that originated and became fixed in a single species, Drosophila melanogaster, within the last 2-3 million years (mys) (10, 11). The sphinx gene was previously identified as a newly evolved chimeric gene (10, 11). The sphinx gene was formed by the insertion of a retroposed sequence of the ATP synthase F-chain gene (ATPS-F) from chromosome 2 into the 102F region of chromosome 4, recruiting sequences upstream to form a new exon and intron, a region we refer to as 102F-EI (10). Two alternative transcripts in adult males were detected from this locus (10). The sphinx gene appears to be functional because the gene contains only indel polymorphisms in the nonexonic sequences; it has a rate of evolution significantly above neutral expectations, suggesting rapid adaptive evolution; and it has a very specific pattern of expression (10). However, although it is derived, in part, from a protein-coding gene, it is most likely a noncoding RNA (ncRNA) because its parental-inherited coding regions are disrupted b...

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“…41 Moreover, mRNA turnover pathways, such as the Nonstop mRNA decay, often target mRNAs with long 3 0 UTRs for degradation. 43 These observations suggest that a nonsense suppression strategy could be applied with a reduced toxic effect resulting from readthrough of canonical stop codons.…”

Section: Resultsmentioning

confidence: 99%

Rescue of wild-type E-cadherin expression from nonsense-mutated cancer cells by a suppressor-tRNA

et al. 2014

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Hereditary diffuse gastric cancer (HDGC) syndrome, although rare, is highly penetrant at an early age, and is severe and incurable because of ineffective screening tools and therapy. Approximately 45% of HDGC families carry germline CDH1/Ecadherin alterations, 20% of which are nonsense leading to premature protein truncation. Prophylactic gastrectomy is the only recommended approach for all asymptomatic CDH1 mutation carriers. Suppressor-tRNAs can replace premature stop codons (PTCs) with a cognate amino acid, inducing readthrough and generating full-length proteins. The use of suppressor-tRNAs in HDGC patients could therefore constitute a less invasive therapeutic option for nonsense mutation carriers, delaying the development of gastric cancer. Our analysis revealed that 23/108 (21.3%) of E-cadherin-mutant families carried nonsense mutations that could be potentially corrected by eight suppressor-tRNAs, and arginine was the most frequently affected amino acid. Using site-directed mutagenesis, we developed an arginine suppressor-tRNA vector to correct one HDGC nonsense mutation. E-cadherin-deficient cell lines were transfected with plasmids carrying simultaneously the suppressor-tRNA and wild-type or mutant CDH1 mini-genes. RT-PCR, western blot, immunofluorescence, flow cytometry and proximity ligation assay (PLA) were used to establish the model, and monitor mRNA and protein expression and function recovery from CDH1 vectors. Cells expressing a CDH1 mini-gene, carrying a nonsense mutation and the suppressor-tRNA, recovered full-length E-cadherin expression and its correct localization and incorporation into the adhesion complex. This is the first demonstration of functional recovery of a mutated causative gene in hereditary cancer by cognate amino acid replacement with suppressor-tRNAs. Of the HDGC families, 21.3% are candidates for correction with suppressor-tRNAs to potentially delay cancer onset.

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An mRNA Surveillance Mechanism That Eliminates Transcripts Lacking Termination Codons

Cited by 498 publications

References 20 publications

Genetic interactions between [ PSI ⁺ ] and nonstop mRNA decay affect phenotypic variation

Genetic interactions between [ PSI ⁺ ] and nonstop mRNA decay affect phenotypic variation

The evolution of courtship behaviors through the origination of a new gene in Drosophila

Rescue of wild-type E-cadherin expression from nonsense-mutated cancer cells by a suppressor-tRNA

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An mRNA Surveillance Mechanism That Eliminates Transcripts Lacking Termination Codons

Cited by 498 publications

References 20 publications

Genetic interactions between [ PSI + ] and nonstop mRNA decay affect phenotypic variation

Genetic interactions between [ PSI + ] and nonstop mRNA decay affect phenotypic variation

The evolution of courtship behaviors through the origination of a new gene in Drosophila

Rescue of wild-type E-cadherin expression from nonsense-mutated cancer cells by a suppressor-tRNA

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Genetic interactions between [ PSI ⁺ ] and nonstop mRNA decay affect phenotypic variation

Genetic interactions between [ PSI ⁺ ] and nonstop mRNA decay affect phenotypic variation