Recognition of nonsense mRNA: towards a unified model

2008 ◽  
Vol 36 (3) ◽  
pp. 497-501 ◽  
Author(s):  
Oliver Mühlemann
Keyword(s):  
Gene Expression ◽  
Present Article ◽  
Protein Complex ◽  
Mrna Decay ◽  
Translation Termination ◽  
Physical Distance ◽  
Unified Model ◽  
Nonsense Mediated Mrna Decay ◽  
Correct Translation ◽  
Premature Translation Termination

Among the different cellular surveillance mechanisms that ensure accurate gene expression, nonsense-mediated mRNA decay rapidly degrades mRNAs harbouring PTCs (premature translation-termination codons) and thereby prevents the accumulation of potentially deleterious proteins with C-terminal truncations. In the present article, I review recent data from yeast, fluitflies, nematode worms and human cells and endeavour to merge these results into a unified model for recognition of nonsense mRNA. According to this model, the distinction between translation termination at PTCs and at ‘normal’ termination codons relies on the physical distance between the terminating ribosome and PABP [poly(A)-binding protein]. Correct translation termination is promoted by a PABP-mediated signal to the terminating ribosome, whereas the absence of this signal leads to the assembly of an mRNA decay-promoting protein complex including the conserved NMD factors UPF (up-frameshift) 1–3.

scholarly journals A UPF1 variant drives conditional remodeling of nonsense-mediated mRNA decay

2021 ◽  
Author(s):  
Sarah E. Fritz ◽  
Soumya Ranganathan ◽  
J. Robert Hogg
Keyword(s):  
Gene Expression ◽  
Mrna Decay ◽  
Gene Expression Regulation ◽  
Translation Termination ◽  
Translational Repression ◽  
The Core ◽  
Human Genes ◽  
Rna Quality Control ◽  
Nonsense Mediated Mrna Decay

AbstractThe nonsense-mediated mRNA decay (NMD) pathway monitors translation termination to degrade transcripts with premature stop codons and regulate thousands of human genes. Due to the major role of NMD in RNA quality control and gene expression regulation, it is important to understand how the pathway responds to changing cellular conditions. Here we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1LL, enables condition-dependent remodeling of NMD specificity. UPF1LL associates more stably with potential NMD target mRNAs than the major UPF1SL isoform, expanding the scope of NMD to include many transcripts normally immune to the pathway. Unexpectedly, the enhanced persistence of UPF1LL on mRNAs supports induction of NMD in response to rare translation termination events. Thus, while canonical NMD is abolished by translational repression, UPF1LL activity is enhanced, providing a mechanism to rapidly rewire NMD specificity in response to cellular stress.

scholarly journals Gene expression networks: competing mRNA decay pathways in mammalian cells

2009 ◽  
Vol 37 (6) ◽  
pp. 1287-1292 ◽  
Author(s):  
Lynne E. Maquat ◽  
Chenguang Gong
Keyword(s):  
Gene Expression ◽  
Present Article ◽  
Mammalian Cells ◽  
Mrna Decay ◽  
C2c12 Myoblasts ◽  
Nonsense Mediated Mrna Decay ◽  
Multinucleated Myotubes

Nonsense-mediated mRNA decay and Staufen1-mediated mRNA decay are mechanistically related pathways that serve distinct purposes. In the present article, we give an overview of each pathway. We describe how a factor that is common to both pathways results in their competition. We also explain how competition between the two pathways contributes to the differentiation of C2C12 myoblasts to multinucleated myotubes.

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.

scholarly journals Nonsense-mediated mRNA decay relies on “two-factor authentication” by SMG5-SMG7

2020 ◽  
Author(s):  
Volker Boehm ◽  
Sabrina Kueckelmann ◽  
Jennifer V. Gerbracht ◽  
Thiago Britto-Borges ◽  
Janine Altmüller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Decay ◽  
Translation Termination ◽  
Mrna Degradation ◽  
Eukaryotic Gene Expression ◽  
Eukaryotic Gene ◽  
Nonsense Mediated Mrna Decay ◽  
Functional Hierarchy ◽  
Improved Model ◽  
Dependent Pathway

AbstractEukaryotic gene expression is constantly regulated and controlled by the translation-coupled nonsense-mediated mRNA decay (NMD) pathway. Aberrant translation termination leads to NMD activation and robust clearance of NMD targets via two seemingly independent and redundant mRNA degradation branches. Here, we uncover that the loss of the first SMG5-SMG7-dependent pathway also inactivates the second SMG6-dependent branch, indicating an unexpected functional hierarchy of the final NMD steps. Transcriptome-wide analyses of SMG5-SMG7-depleted cells confirm complete NMD inhibition resulting in massive transcriptomic alterations. The NMD activity conferred by SMG5-SMG7 is determined to varying degrees by their interaction with the central NMD factor UPF1, heterodimer formation and the initiation of deadenylation. Surprisingly, we find that SMG5 functionally substitutes SMG7 and vice versa. Our data support an improved model for NMD execution that requires two-factor authentication involving UPF1 phosphorylation and SMG5-SMG7 recruitment to access SMG6 activity.

UPF1 P-body localization

2008 ◽  
Vol 36 (4) ◽  
pp. 698-700 ◽  
Author(s):  
Saverio Brogna ◽  
Preethi Ramanathan ◽  
Jikai Wen
Keyword(s):  
Mrna Decay ◽  
Translation Termination ◽  
Processing Bodies ◽  
Cytoplasmic Granules ◽  
P Bodies ◽  
The Core ◽  
Nonsense Mediated Mrna Decay ◽  
Premature Translation Termination

NMD (nonsense-mediated mRNA decay) is a mechanism that degrades transcripts containing PTCs (premature translation termination codons). NMD is a translation-associated process that is expected to take place throughout the cytoplasm. However, recent studies have indicated that the core NMD factors UPF1 (up-frameshift-1), UPF2 and UPF3 can associate with P-bodies (processing bodies), which are large cytoplasmic granules replete with proteins involved in general mRNA decay and related processes. It has been proposed that UPF1 directs PTC-containing mRNAs to P-bodies and triggers decay. Here, we discuss the link between P-bodies and NMD in view of recent studies that suggest that P-bodies are not required for NMD in Drosophila.

scholarly journals Regulation of Multiple Core Spliceosomal Proteins by Alternative Splicing-Coupled Nonsense-Mediated mRNA Decay

2008 ◽  
Vol 28 (13) ◽  
pp. 4320-4330 ◽  
Author(s):  
Arneet L. Saltzman ◽  
Yoon Ki Kim ◽  
Qun Pan ◽  
Matthew M. Fagnani ◽  
Lynne E. Maquat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Mrna Decay ◽  
Splice Variants ◽  
Cellular Functions ◽  
Regulate Gene Expression ◽  
Premature Termination Codons ◽  
Microarray Profiling ◽  
Nonsense Mediated Mrna Decay ◽  
Regulate Gene

ABSTRACT Alternative splicing (AS) can regulate gene expression by introducing premature termination codons (PTCs) into spliced mRNA that subsequently elicit transcript degradation by the nonsense-mediated mRNA decay (NMD) pathway. However, the range of cellular functions controlled by this process and the factors required are poorly understood. By quantitative AS microarray profiling, we find that there are significant overlaps among the sets of PTC-introducing AS events affected by individual knockdown of the three core human NMD factors, Up-Frameshift 1 (UPF1), UPF2, and UPF3X/B. However, the levels of some PTC-containing splice variants are less or not detectably affected by the knockdown of UPF2 and/or UPF3X, compared with the knockdown of UPF1. The intron sequences flanking the affected alternative exons are often highly conserved, suggesting important regulatory roles for these AS events. The corresponding genes represent diverse cellular functions, and surprisingly, many encode core spliceosomal proteins and assembly factors. We further show that conserved, PTC-introducing AS events are enriched in genes that encode core spliceosomal proteins. Where tested, altering the expression levels of these core spliceosomal components affects the regulation of PTC-containing splice variants from the corresponding genes. Together, our results show that AS-coupled NMD can have different UPF factor requirements and is likely to regulate many general components of the spliceosome. The results further implicate general spliceosomal components in AS regulation.

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.

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