Cutting the nonsense: the degradation of PTC-containing mRNAs

2010 ◽  
Vol 38 (6) ◽  
pp. 1615-1620 ◽  
Author(s):  
Pamela Nicholson ◽  
Oliver Mühlemann
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Quality Control ◽  
Control Function ◽  
Translation Termination ◽  
Rapid Degradation ◽  
Morphological Defects ◽  
Nonsense Mediated Mrna Decay ◽  
Specific Factors ◽  
Transcriptional Pathway ◽  
Premature Translation Termination

In eukaryotes, mRNAs harbouring PTCs (premature translation-termination codons) are recognized and eliminated by NMD (nonsense-mediated mRNA decay). In addition to its quality-control function, NMD constitutes a translation-dependent post-transcriptional pathway to regulate the expression levels of physiological mRNAs. In contrast with PTC recognition, little is known about the mechanisms that trigger the rapid degradation of mammalian nonsense mRNA. Studies have shown that mammalian NMD targets can be degraded via both an SMG6 (where SMG is suppressor of morphological defects on genitalia)-dependent endonucleolytic pathway and a deadenylation and decapping-dependent exonucleolytic pathway, with the possible involvement of SMG5 and SMG7. In contrast, Drosophila melanogaster NMD is confined to the former and Saccharomyces cerevisiae NMD to the latter decay pathway. Consistent with this conclusion, mammals possess both SMG6 and SMG7, whereas D. melanogaster lacks an SMG7 homologue and yeast have no SMG6 equivalent. In the present paper, we review what is known about the degradation of PTC-containing mRNAs so far, paying particular attention to the properties of the NMD-specific factors SMG5–SMG7 and to what is known about the mechanism of degrading mRNAs after they have been committed to the NMD pathway.

scholarly journals Upf1p, Nmd2p, and Upf3p Regulate the Decapping and Exonucleolytic Degradation of both Nonsense-Containing mRNAs and Wild-Type mRNAs

2001 ◽  
Vol 21 (5) ◽  
pp. 1515-1530 ◽  
Author(s):  
Feng He ◽  
Allan Jacobson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mrna Decay ◽  
Translation Termination ◽  
Mrna Degradation ◽  
Wild Type ◽  
Rapid Degradation ◽  
Yeast Strains ◽  
Nonsense Mediated Mrna Decay ◽  
Exonucleolytic Degradation ◽  
Decapping Enzyme

ABSTRACT In Saccharomyces cerevisiae, rapid degradation of nonsense-containing mRNAs requires the decapping enzyme Dcp1p, the 5′-to-3′ exoribonuclease Xrn1p, and the three nonsense-mediated mRNA decay (NMD) factors, Upf1p, Nmd2p, and Upf3p. To identify specific functions for the NMD factors, we analyzed the mRNA decay phenotypes of yeast strains containing deletions of DCP1 orXRN1 and UPF1, NMD2, or UPF3. Our results indicate that Upf1p, Nmd2p, and Upf3p regulate decapping and exonucleolytic degradation of nonsense-containing mRNAs. In addition, we show that these factors also regulate the same processes in the degradation of wild-type mRNAs. The participation of the NMD factors in general mRNA degradation suggests that they may regulate an aspect of translation termination common to all transcripts.

scholarly journals Inhibition of post-termination ribosome recycling at premature termination codons in UPF1 ATPase mutants

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Lucas D Serdar ◽  
DaJuan L Whiteside ◽  
Sarah L Nock ◽  
David McGrath ◽  
Kristian E Baker
Keyword(s):  
Active Site ◽  
Translation Termination ◽  
Rna Helicase ◽  
Rna Decay ◽  
Functional Interaction ◽  
Rapid Degradation ◽  
Premature Termination Codons ◽  
Nonsense Mediated Mrna Decay ◽  
Inactivating Mutation ◽  
Premature Translation Termination

Recognition and rapid degradation of mRNA harboring premature translation termination codons (PTCs) serves to protect cells from accumulating non-functional and potentially toxic truncated polypeptides. Targeting of PTC-containing transcripts is mediated by the nonsense-mediated mRNA decay (NMD) pathway and requires a conserved set of proteins including UPF1, an RNA helicase whose ATPase activity is essential for NMD. Previously, we identified a functional interaction between the NMD machinery and terminating ribosomes based on 3’ RNA decay fragments that accrue in UPF1 ATPase mutants. Herein, we show that those decay intermediates originate downstream of the PTC and harbor 80S ribosomes that migrate into the mRNA 3’ UTR independent of canonical translation. Accumulation of 3’ RNA decay fragments is determined by both RNA sequence downstream of the PTC and the inactivating mutation within the active site of UPF1. Our data reveal a failure in post-termination ribosome recycling in UPF1 ATPase mutants.

scholarly journals Caenorhabditis elegans SMG-2 Selectively Marks mRNAs Containing Premature Translation Termination Codons

2007 ◽  
Vol 27 (16) ◽  
pp. 5630-5638 ◽  
Author(s):  
Lisa Johns ◽  
Andrew Grimson ◽  
Sherry L. Kuchma ◽  
Carrie Loushin Newman ◽  
Philip Anderson
Keyword(s):  
Caenorhabditis Elegans ◽  
Mammalian Cells ◽  
Translation Termination ◽  
Yeast Two Hybrid ◽  
Eukaryotic Mrnas ◽  
Nonsense Mediated Mrna Decay ◽  
Endogenous Genes ◽  
Alternatively Spliced ◽  
Two Hybrid ◽  
Premature Translation Termination

ABSTRACT Eukaryotic mRNAs containing premature translation termination codons (PTCs) are rapidly degraded by a process termed “nonsense-mediated mRNA decay” (NMD). We examined protein-protein and protein-RNA interactions among Caenorhabditis elegans proteins required for NMD. SMG-2, SMG-3, and SMG-4 are orthologs of yeast (Saccharomyces cerevisiae) and mammalian Upf1, Upf2, and Upf3, respectively. A combination of immunoprecipitation and yeast two-hybrid experiments indicated that SMG-2 interacts with SMG-3, SMG-3 interacts with SMG-4, and SMG-2 interacts indirectly with SMG-4 via shared interactions with SMG-3. Such interactions are similar to those observed in yeast and mammalian cells. SMG-2-SMG-3-SMG-4 interactions require neither SMG-2 phosphorylation, which is abolished in smg-1 mutants, nor SMG-2 dephosphorylation, which is reduced or eliminated in smg-5 mutants. SMG-2 preferentially associates with PTC-containing mRNAs. We monitored the association of SMG-2, SMG-3, and SMG-4 with mRNAs of five endogenous genes whose mRNAs are alternatively spliced to either contain or not contain PTCs. SMG-2 associates with both PTC-free and PTC-containing mRNPs, but it strongly and preferentially associates with (“marks”) those containing PTCs. SMG-2 marking of PTC-mRNPs is enhanced by SMG-3 and SMG-4, but SMG-3 and SMG-4 are not detectably associated with the same mRNPs. Neither SMG-2 phosphorylation nor dephosphorylation is required for selective association of SMG-2 with PTC-containing mRNPs, indicating that SMG-2 is phosphorylated only after premature terminations have been discriminated from normal terminations. We discuss these observations with regard to the functions of SMG-2 and its phosphorylation during NMD.

scholarly journals Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia

2020 ◽  
Vol 9 (2) ◽  
pp. 289 ◽  
Author(s):  
Monica Borgatti ◽  
Emiliano Altamura ◽  
Francesca Salvatori ◽  
Elisabetta D’Aversa ◽  
Nicola Altamura
Keyword(s):  
Genetic Disease ◽  
Chelation Therapy ◽  
Translation Termination ◽  
Premature Termination Codon ◽  
Nonsense Suppression ◽  
Current Status ◽  
Nonsense Mutations ◽  
Nonsense Mediated Mrna Decay ◽  
Mrna Destabilization ◽  
Premature Translation Termination

Several types of thalassemia (including β039-thalassemia) are caused by nonsense mutations in genes controlling globin production, leading to premature translation termination and mRNA destabilization mediated by the nonsense mediated mRNA decay. Drugs (for instance, aminoglycosides) can be designed to suppress premature translation termination by inducing readthrough (or nonsense suppression) at the premature termination codon. These findings have introduced new hopes for the development of a pharmacologic approach to cure this genetic disease. In the present review, we first summarize the principle and current status of the chemical relief for the expression of functional proteins from genes otherwise unfruitful for the presence of nonsense mutations. Second, we compare data available on readthrough molecules for β0-thalassemia. The examples reported in the review strongly suggest that ribosomal readthrough should be considered as a therapeutic approach for the treatment of β0-thalassemia caused by nonsense mutations. Concluding, the discovery of molecules, exhibiting the property of inducing β-globin, such as readthrough compounds, is of great interest and represents a hope for several patients, whose survival will depend on the possible use of drugs rendering blood transfusion and chelation therapy unnecessary.

scholarly journals Tpa1p Is Part of an mRNP Complex That Influences Translation Termination, mRNA Deadenylation, and mRNA Turnover in Saccharomyces cerevisiae

2006 ◽  
Vol 26 (14) ◽  
pp. 5237-5248 ◽  
Author(s):  
Kim M. Keeling ◽  
Joe Salas-Marco ◽  
Lev Z. Osherovich ◽  
David M. Bedwell
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mrna Decay ◽  
Potential Role ◽  
Translation Termination ◽  
Tail Length ◽  
Fold Increase ◽  
Reading Frame ◽  
Yeast Strains ◽  
Messenger Ribonucleoprotein ◽  
Nonsense Mediated Mrna Decay

ABSTRACT In this report, we show that the Saccharomyces cerevisiae protein Tpa1p (for termination and polyadenylation) influences translation termination efficiency, mRNA poly(A) tail length, and mRNA stability. Tpa1p is encoded by the previously uncharacterized open reading frame YER049W. Yeast strains carrying a deletion of the TPA1 gene (tpa1Δ) exhibited increased readthrough of stop codons, and coimmunoprecipitation assays revealed that Tpa1p interacts with the translation termination factors eRF1 and eRF3. In addition, the tpa1Δ mutation led to a 1.5- to 2-fold increase in the half-lives of mRNAs degraded by the general 5′→3′ pathway or the 3′→5′ nonstop decay pathway. In contrast, this mutation did not have any affect on the nonsense-mediated mRNA decay pathway. Examination of mRNA poly(A) tail length revealed that poly(A) tails are longer than normal in a tpa1Δ strain. Consistent with a potential role in regulating poly(A) tail length, Tpa1p was also found to coimmunoprecipitate with the yeast poly(A) binding protein Pab1p. These results suggest that Tpa1p is a component of a messenger ribonucleoprotein complex bound to the 3′ untranslated region of mRNAs that affects translation termination, deadenylation, and mRNA decay.

scholarly journals Gene Set Coregulated by the Saccharomyces cerevisiae Nonsense-Mediated mRNA Decay Pathway

2005 ◽  
Vol 4 (12) ◽  
pp. 2066-2077 ◽  
Author(s):  
Rachel Taylor ◽  
Bessie Wanja Kebaara ◽  
Tara Nazarenus ◽  
Ashley Jones ◽  
Rena Yamanaka ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mrna Decay ◽  
Translation Termination ◽  
Yeast Cells ◽  
Wild Type ◽  
Transcription Activator ◽  
Nonsense Mediated Mrna Decay ◽  
Indirect Consequence ◽  
Transcription Activators ◽  
And Function

ABSTRACT The nonsense-mediated mRNA decay (NMD) pathway has historically been thought of as an RNA surveillance system that degrades mRNAs with premature translation termination codons, but the NMD pathway of Saccharomyces cerevisiae has a second role regulating the decay of some wild-type mRNAs. In S. cerevisiae, a significant number of wild-type mRNAs are affected when NMD is inactivated. These mRNAs are either wild-type NMD substrates or mRNAs whose abundance increases as an indirect consequence of NMD. A current challenge is to sort the mRNAs that accumulate when NMD is inactivated into direct and indirect targets. We have developed a bioinformatics-based approach to address this challenge. Our approach involves using existing genomic and function databases to identify transcription factors whose mRNAs are elevated in NMD-deficient cells and the genes that they regulate. Using this strategy, we have investigated a coregulated set of genes. We have shown that NMD regulates accumulation of ADR1 and GAL4 mRNAs, which encode transcription activators, and that Adr1 is probably a transcription activator of ATS1. This regulation is physiologically significant because overexpression of ADR1 causes a respiratory defect that mimics the defect seen in strains with an inactive NMD pathway. This strategy is significant because it allows us to classify the genes regulated by NMD into functionally related sets, an important step toward understanding the role NMD plays in the normal functioning of yeast cells.

Nonsense-mediated mRNA decay

2008 ◽  
Vol 36 (3) ◽  
pp. 514-516 ◽  
Author(s):  
Jikai Wen ◽  
Saverio Brogna
Keyword(s):  
Mammalian Cells ◽  
Mrna Decay ◽  
Translation Termination ◽  
Mrna Splicing ◽  
Current Understanding ◽  
Coupled Processes ◽  
Recent Developments ◽  
Nonsense Mediated Mrna Decay ◽  
Premature Translation Termination

Translation and mRNA decay are coupled processes; the link is most obvious in the case of NMD (nonsense-mediated mRNA decay). NMD is a mechanism that drastically reduces the level of mRNA harbouring PTCs (premature translation termination codons). The defining event in NMD is premature translation termination and the key question is: what distinguishes premature from normal translation termination? Surprisingly, in mammalian cells, PTC recognition is linked to pre-mRNA splicing. Here, we review the current understanding in view of recent developments.

scholarly journals Nonsense-Mediated mRNA Decay Effectors Are Essential for Zebrafish Embryonic Development and Survival

2009 ◽  
Vol 29 (13) ◽  
pp. 3517-3528 ◽  
Author(s):  
Nadine Wittkopp ◽  
Eric Huntzinger ◽  
Catrin Weiler ◽  
Jérôme Saulière ◽  
Steffen Schmidt ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Mrna Decay ◽  
Cultured Cells ◽  
Translation Termination ◽  
Zebrafish Genome ◽  
Zebrafish Embryos ◽  
Nonsense Mediated Mrna Decay ◽  
Nonsense Codons ◽  
Zebrafish Embryogenesis ◽  
Premature Translation Termination

ABSTRACT The nonsense-mediated mRNA decay (NMD) pathway promotes rapid degradation of mRNAs containing premature translation termination codons (PTCs or nonsense codons), preventing accumulation of potentially detrimental truncated proteins. In metazoa, seven genes (upf1, upf2, upf3, smg1, smg5, smg6, and smg7) have been identified as essential for NMD; here we show that the zebrafish genome encodes orthologs of upf1, upf2, smg1, and smg5 to smg7 and two upf3 paralogs. We also show that Upf1 is required for degradation of PTC-containing mRNAs in zebrafish embryos. Moreover, its depletion has a severe impact on embryonic development, early patterning, and viability. Similar phenotypes are observed in Upf2-, Smg5-, or Smg6-depleted embryos, suggesting that zebrafish embryogenesis requires an active NMD pathway. Using cultured cells, we demonstrate that the ability of a PTC to trigger NMD is strongly stimulated by downstream exon-exon boundaries. Thus, as in mammals and plants but in contrast to invertebrates and fungi, NMD is coupled to splicing in zebrafish. Our results together with previous studies show that NMD effectors are essential for vertebrate embryogenesis and suggest that the coupling of splicing and NMD has been maintained in vertebrates but lost in fungi and invertebrates.

Ribosome‐associated quality control mediates degradation of the premature translation termination product Orf1p of ODC antizyme mRNA

FEBS Letters ◽  
2021 ◽  
Author(s):  
Ashis Kumar Pradhan ◽  
Ganapathi Kandasamy ◽  
Upasana Chatterjee ◽  
Anushree Bharadwaj ◽  
Sam J. Mathew ◽  
...  
Keyword(s):  
Quality Control ◽  
Translation Termination ◽  
Premature Translation Termination
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