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

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.

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

Molecular and Cellular Biology ◽

10.1128/mcb.00410-07 ◽

2007 ◽

Vol 27 (16) ◽

pp. 5630-5638 ◽

Cited By ~ 39

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.

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MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNALys and premature translation termination

Nature Genetics ◽

10.1038/ng0595-47 ◽

1995 ◽

Vol 10 (1) ◽

pp. 47-55 ◽

Cited By ~ 192

Author(s):

José Antonio Enriquez ◽

Anne Chomyn ◽

Giuseppe Attardi

Keyword(s):

Translation Termination ◽

Mtdna Mutation ◽

Merrf Syndrome ◽

Premature Translation Termination

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BCR-ABL Truncation due to Premature Translation Termination as a Mechanism of Resistance to Kinase Inhibitors

Acta Haematologica ◽

10.1159/000210060 ◽

2009 ◽

Vol 121 (1) ◽

pp. 27-31 ◽

Cited By ~ 15

Author(s):

Wanlong Ma ◽

Hagop Kantarjian ◽

Chen-Hsiung Yeh ◽

Zhong J. Zhang ◽

Jorge Cortes ◽

...

Keyword(s):

Kinase Inhibitors ◽

Translation Termination ◽

Mechanism Of Resistance ◽

Premature Translation Termination

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

Journal of Clinical Medicine ◽

10.3390/jcm9020289 ◽

2020 ◽

Vol 9 (2) ◽

pp. 289 ◽

Cited By ~ 3

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.

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The Origin and Evolution of Release Factors: Implications for Translation Termination, Ribosome Rescue and Quality Control Pathways

10.20944/preprints201904.0061.v1 ◽

2019 ◽

Author(s):

A.Maxwell Burroughs ◽

L Aravind

Keyword(s):

Quality Control ◽

Translation Termination ◽

Last Universal Common Ancestor ◽

Origin And Evolution ◽

Release Factors ◽

Universal Common Ancestor ◽

Translation Apparatus ◽

Ph Domains ◽

Evolutionary Trajectories ◽

Hydrolysis Of

The evolution of release factors catalyzing the hydrolysis of the final peptidyl-tRNA bond and the release of the polypeptide from the ribosome has been a longstanding paradox. While the components of the translation apparatus are generally well-conserved across extant life, structurally-unrelated release factor peptidyl hydrolases (RF-PHs) emerged in the stems of the bacterial and archaeo-eukaryotic lineages. We analyze the diversification of RF-PH domains within the broader evolutionary framework of the translation apparatus. Thus, we reconstruct the possible state of translation termination in the Last Universal Common Ancestor with possible tRNA-like terminators. Further, evolutionary trajectories of the several auxiliary release factors in ribosome quality control (RQC) and rescue pathways point to multiple independent solutions to this problem and frequent transfers between superkingdoms including the recently-characterized ArfT, which is more widely-distributed across life than previously appreciated. The eukaryotic RQC system was pieced together from components with disparate provenance, which include the long-sought Vms1/ANKZF1 RF-PH of bacterial origin. We also uncover an under-appreciated evolutionary driver of innovation in rescue pathways: effectors deployed in biological conflicts that target the ribosome. At least three rescue pathways (centered on the prfH/RFH, baeRF-1, and C12orf65 RF-PH domains), were likely innovated in response to such conflicts.

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Intranuclear defect in beta-globin mRNA accumulation due to a premature translation termination codon

Blood ◽

10.1182/blood.v64.1.13.13 ◽

1984 ◽

Vol 64 (1) ◽

pp. 13-22 ◽

Cited By ~ 47

Author(s):

K Takeshita ◽

BG Forget ◽

A Scarpa ◽

EJ Jr Benz

Keyword(s):

Translation Termination ◽

Beta Globin ◽

Mrna Synthesis ◽

Globin Mrna ◽

Mrna Accumulation ◽

S1 Nuclease ◽

Translation Termination Codon ◽

Premature Translation Termination ◽

Premature Translation Termination Codon

Abstract We have analyzed a cloned beta O-thalassemia (beta O-thal) gene from a patient doubly heterozygous for hemoglobin Lepore and beta O- thalassemia. Studies of 3H-uridine incorporation into beta-globin mRNA in this patient's erythroblasts suggested an intranuclear defect in both beta and Lepore (delta beta) mRNA synthesis, as did S1 nuclease analysis of nuclear RNA. However, the nucleotide sequence of the beta O- thal gene revealed only a single base change in codon 39 (CAG----UAG), which created a premature translation termination codon. The 5′ flanking sequence, including transcription promotor boxes and the mRNA initiation (CAP) site, were normal. The unexpected effect of this mutation on intranuclear beta-mRNA synthesis in vivo was studied by insertion of the cloned gene into a plasmid expression vector and transfection into tissue culture (COS-1) cells. beta-Globin mRNA produced by the transfected cells was assessed by S1 nuclease analysis. The beta O-39 thalassemia gene generated five- to tenfold less beta- mRNA than a normal beta-gene in both nuclear and cytoplasmic RNA, simulating the results observed in vivo. Moreover, the small amount of beta O-39 mRNA produced was as stable as normal beta-mRNA during an actinomycin D chase, ruling out rapid cytoplasmic turnover as a cause of the reduced accumulation. Cotransfection of the beta O-39 thalassemia gene with a mutant tyrosine suppressor tRNA gene resulted in restoration of the beta O-39 mRNA accumulation to near-normal levels. On the basis of these results, we suggest that the low levels of beta-mRNA known to exist in the common form of beta O-thalassemia, beta O-39 thalassemia, result from a lesion in transcription, or early posttranscriptional processes; the defect appears to be corrected by restoration of proper translational potential to the mutant mRNA, at least in a gene transfer-expression system in tissue-culture cells.

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Nonsense-mediated mRNA decay

Biochemical Society Transactions ◽

10.1042/bst0360514 ◽

2008 ◽

Vol 36 (3) ◽

pp. 514-516 ◽

Cited By ~ 25

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.

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

Molecular and Cellular Biology ◽

10.1128/mcb.00177-09 ◽

2009 ◽

Vol 29 (13) ◽

pp. 3517-3528 ◽

Cited By ~ 117

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.

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Intranuclear defect in beta-globin mRNA accumulation due to a premature translation termination codon

Blood ◽

10.1182/blood.v64.1.13.bloodjournal64113 ◽

1984 ◽

Vol 64 (1) ◽

pp. 13-22

Author(s):

K Takeshita ◽

BG Forget ◽

A Scarpa ◽

EJ Jr Benz

Keyword(s):

Translation Termination ◽

Beta Globin ◽

Mrna Synthesis ◽

Globin Mrna ◽

Mrna Accumulation ◽

S1 Nuclease ◽

Translation Termination Codon ◽

Premature Translation Termination ◽

Premature Translation Termination Codon

We have analyzed a cloned beta O-thalassemia (beta O-thal) gene from a patient doubly heterozygous for hemoglobin Lepore and beta O- thalassemia. Studies of 3H-uridine incorporation into beta-globin mRNA in this patient's erythroblasts suggested an intranuclear defect in both beta and Lepore (delta beta) mRNA synthesis, as did S1 nuclease analysis of nuclear RNA. However, the nucleotide sequence of the beta O- thal gene revealed only a single base change in codon 39 (CAG----UAG), which created a premature translation termination codon. The 5′ flanking sequence, including transcription promotor boxes and the mRNA initiation (CAP) site, were normal. The unexpected effect of this mutation on intranuclear beta-mRNA synthesis in vivo was studied by insertion of the cloned gene into a plasmid expression vector and transfection into tissue culture (COS-1) cells. beta-Globin mRNA produced by the transfected cells was assessed by S1 nuclease analysis. The beta O-39 thalassemia gene generated five- to tenfold less beta- mRNA than a normal beta-gene in both nuclear and cytoplasmic RNA, simulating the results observed in vivo. Moreover, the small amount of beta O-39 mRNA produced was as stable as normal beta-mRNA during an actinomycin D chase, ruling out rapid cytoplasmic turnover as a cause of the reduced accumulation. Cotransfection of the beta O-39 thalassemia gene with a mutant tyrosine suppressor tRNA gene resulted in restoration of the beta O-39 mRNA accumulation to near-normal levels. On the basis of these results, we suggest that the low levels of beta-mRNA known to exist in the common form of beta O-thalassemia, beta O-39 thalassemia, result from a lesion in transcription, or early posttranscriptional processes; the defect appears to be corrected by restoration of proper translational potential to the mutant mRNA, at least in a gene transfer-expression system in tissue-culture cells.

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