scholarly journals Mechanism of premature translation termination on a sense codon

2018 ◽  
Vol 293 (32) ◽  
pp. 12472-12479 ◽  
Author(s):  
Egor Svidritskiy ◽  
Gabriel Demo ◽  
Andrei A. Korostelev
Keyword(s):  
Translation Termination ◽  
Sense Codon ◽  
Premature Translation Termination

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

2009 ◽  
Vol 121 (1) ◽  
pp. 27-31 ◽  
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

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

Blood ◽  
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

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.

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

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

Blood ◽  
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.

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.

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