To see the other types of publications on this topic, follow the link: NMD.
Journal articles on the topic 'NMD'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'NMD.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Domingo, Deepti, Urwah Nawaz, Mark Corbett, Josh L. Espinoza, Katrina Tatton-Brown, David Coman, Miles F. Wilkinson, Jozef Gecz, and Lachlan A. Jolly. "A synonymous UPF3B variant causing a speech disorder implicates NMD as a regulator of neurodevelopmental disorder gene networks." Human Molecular Genetics 29, no. 15 (July 16, 2020): 2568–78. http://dx.doi.org/10.1093/hmg/ddaa151.
Full textAbstract:
Abstract Loss-of-function mutations of the X-chromosome gene UPF3B cause male neurodevelopmental disorders (NDDs) via largely unknown mechanisms. We investigated initially by interrogating a novel synonymous UPF3B variant in a male with absent speech. In silico and functional studies using cell lines derived from this individual show altered UPF3B RNA splicing. The resulting mRNA species encodes a frame-shifted protein with a premature termination codon (PTC) predicted to elicit degradation via nonsense-mediated mRNA decay (NMD). UPF3B mRNA was reduced in the cell line, and no UPF3B protein was produced, confirming a loss-of-function allele. UPF3B is itself involved in the NMD mechanism which degrades both PTC-bearing mutant transcripts and also many physiological transcripts. RNAseq analysis showed that ~1.6% of mRNAs exhibited altered expression. These mRNA changes overlapped and correlated with those we identified in additional cell lines obtained from individuals harbouring other UPF3B mutations, permitting us to interrogate pathogenic mechanisms of UPF3B-associated NDDs. We identified 102 genes consistently deregulated across all UPF3B mutant cell lines. Of the 51 upregulated genes, 75% contained an NMD-targeting feature, thus identifying high-confidence direct NMD targets. Intriguingly, 22 of the dysregulated genes encoded known NDD genes, suggesting UPF3B-dependent NMD regulates gene networks critical for cognition and behaviour. Indeed, we show that 78.5% of all NDD genes encode a transcript predicted to be targeted by NMD. These data describe the first synonymous UPF3B mutation in a patient with prominent speech and language disabilities and identify plausible mechanisms of pathology downstream of UPF3B mutations involving the deregulation of NDD-gene networks.
2
Kim, Eunha, and Jun R. Huh. "NMD Takes the Immune Road to NDD." Neuron 104, no. 4 (November 2019): 625–26. http://dx.doi.org/10.1016/j.neuron.2019.10.042.
Full text
3
Ghosh, P. K. "Naval NMD: The concept of expanding NMD seawards*." Strategic Analysis 25, no. 8 (November 2001): 897–919. http://dx.doi.org/10.1080/09700160108459007.
Full text
4
Udy, Dylan B., and Robert K. Bradley. "Nonsense-mediated mRNA decay uses complementary mechanisms to suppress mRNA and protein accumulation." Life Science Alliance 5, no. 3 (December 8, 2021): e202101217. http://dx.doi.org/10.26508/lsa.202101217.
Full textAbstract:
Nonsense-mediated mRNA decay (NMD) is an essential, highly conserved quality control pathway that detects and degrades mRNAs containing premature termination codons. Although the essentiality of NMD is frequently ascribed to its prevention of truncated protein accumulation, the extent to which NMD actually suppresses proteins encoded by NMD-sensitive transcripts is less well-understood than NMD-mediated suppression of mRNA. Here, we describe a reporter system that permits accurate quantification of both mRNA and protein levels via stable integration of paired reporters encoding NMD-sensitive and NMD-insensitive transcripts into the AAVS1 safe harbor loci in human cells. We use this system to demonstrate that NMD suppresses proteins encoded by NMD-sensitive transcripts by up to eightfold more than the mRNA itself. Our data indicate that NMD limits the accumulation of proteins encoded by NMD substrates by mechanisms beyond mRNA degradation, such that even when NMD-sensitive mRNAs escape destruction, their encoded proteins are still effectively suppressed.
5
Sun, Lingling, Justine Mailliot, and Christiane Schaffitzel. "Nonsense-Mediated mRNA Decay Factor Functions in Human Health and Disease." Biomedicines 11, no. 3 (February 27, 2023): 722. http://dx.doi.org/10.3390/biomedicines11030722.
Full textAbstract:
Nonsense-mediated mRNA decay (NMD) is a cellular surveillance mechanism that degrades mRNAs with a premature stop codon, avoiding the synthesis of C-terminally truncated proteins. In addition to faulty mRNAs, NMD recognises ~10% of endogenous transcripts in human cells and downregulates their expression. The up-frameshift proteins are core NMD factors and are conserved from yeast to human in structure and function. In mammals, NMD diversified into different pathways that target different mRNAs employing additional NMD factors. Here, we review our current understanding of molecular mechanisms and cellular roles of NMD pathways and the involvement of more specialised NMD factors. We describe the consequences of mutations in NMD factors leading to neurodevelopmental diseases, and the role of NMD in cancer. We highlight strategies of RNA viruses to evade recognition and decay by the NMD machinery.
6
Peccarelli, Megan, and Bessie W. Kebaara. "Regulation of Natural mRNAs by the Nonsense-Mediated mRNA Decay Pathway." Eukaryotic Cell 13, no. 9 (July 18, 2014): 1126–35. http://dx.doi.org/10.1128/ec.00090-14.
Full textAbstract:
ABSTRACT The nonsense-mediated mRNA decay (NMD) pathway is a specialized mRNA degradation pathway that degrades select mRNAs. This pathway is conserved in all eukaryotes examined so far, and it triggers the degradation of mRNAs that prematurely terminate translation. Originally identified as a pathway that degrades mRNAs with premature termination codons as a result of errors during transcription, splicing, or damage to the mRNA, NMD is now also recognized as a pathway that degrades some natural mRNAs. The degradation of natural mRNAs by NMD has been identified in multiple eukaryotes, including Saccharomyces cerevisiae , Drosophila melanogaster , Arabidopsis thaliana , and humans. S. cerevisiae is used extensively as a model to study natural mRNA regulation by NMD. Inactivation of the NMD pathway in S. cerevisiae affects approximately 10% of the transcriptome. Similar percentages of natural mRNAs in the D. melanogaster and human transcriptomes are also sensitive to the pathway, indicating that NMD is important for the regulation of gene expression in multiple organisms. NMD can either directly or indirectly regulate the decay rate of natural mRNAs. Direct NMD targets possess NMD-inducing features. This minireview focuses on the regulation of natural mRNAs by the NMD pathway, as well as the features demonstrated to target these mRNAs for decay by the pathway in S. cerevisiae . We also compare NMD-targeting features identified in S. cerevisiae with known NMD-targeting features in other eukaryotic organisms.
7
Chen, Chengyan, Yanmin Shen, Luqian Li, Yaoxin Ren, Zhao-Qi Wang, and Tangliang Li. "UPF3A is dispensable for nonsense-mediated mRNA decay in mouse pluripotent and somatic cells." Life Science Alliance 6, no. 6 (March 30, 2023): e202201589. http://dx.doi.org/10.26508/lsa.202201589.
Full textAbstract:
Nonsense-mediated mRNA decay (NMD) is a highly conserved regulatory mechanism of post-transcriptional gene expression in eukaryotic cells. NMD plays essential roles in mRNA quality and quantity control and thus safeguards multiple biological processes including embryonic stem cell differentiation and organogenesis. UPF3A and UPF3B in vertebrate species, originated from a singleUPF3gene in yeast, are key factors in the NMD machinery. Although UPF3B is a well-recognized weak NMD-promoting factor, whether UPF3A functions in promoting or suppressing NMD is under debate. In this study, we generated aUpf3aconditional knockout mouse strain and established multiple lines of embryonic stem cells and somatic cells without UPF3A. Through extensive analysis on the expressions of 33 NMD targets, we found UPF3A neither represses NMD in mouse embryonic stem cells, somatic cells, nor in major organs including the liver, spleen, and thymus. Our study reinforces that UPF3A is dispensable for NMD when UPF3B is present. Furthermore, UPF3A may weakly and selectively promote NMD in certain murine organs.
8
Lloyd, James P. B. "The evolution and diversity of the nonsense-mediated mRNA decay pathway." F1000Research 7 (August 15, 2018): 1299. http://dx.doi.org/10.12688/f1000research.15872.1.
Full textAbstract:
Nonsense-mediated mRNA decay is a eukaryotic pathway that degrades transcripts with premature termination codons (PTCs). In most eukaryotes, thousands of transcripts are degraded by NMD, including many important regulators of development and stress response pathways. Transcripts can be targeted to NMD by the presence of an upstream ORF or by introduction of a PTC through alternative splicing. Many factors involved in the recognition of PTCs and the destruction of NMD targets have been characterized. While some are highly conserved, others have been repeatedly lost in eukaryotic lineages. Here, I outline the factors involved in NMD, our current understanding of their interactions and how they have evolved. I outline a classification system to describe NMD pathways based on the presence/absence of key NMD factors. These types of NMD pathways exist in multiple different lineages, indicating the plasticity of the NMD pathway through recurrent losses of NMD factors during eukaryotic evolution. By classifying the NMD pathways in this way, gaps in our understanding are revealed, even within well studied organisms. Finally, I discuss the likely driving force behind the origins of the NMD pathway before the appearance of the last eukaryotic common ancestor: transposable element expansion and the consequential origin of introns.
9
Lloyd, James P. B. "The evolution and diversity of the nonsense-mediated mRNA decay pathway." F1000Research 7 (November 22, 2018): 1299. http://dx.doi.org/10.12688/f1000research.15872.2.
Full textAbstract:
Nonsense-mediated mRNA decay is a eukaryotic pathway that degrades transcripts with premature termination codons (PTCs). In most eukaryotes, thousands of transcripts are degraded by NMD, including many important regulators of developmental and stress response pathways. Transcripts can be targeted to NMD by the presence of an upstream ORF or by introduction of a PTC through alternative splicing. Many factors involved in the recognition of PTCs and the destruction of NMD targets have been characterized. While some are highly conserved, others have been repeatedly lost in eukaryotic lineages. Here, I detail the factors involved in NMD, our current understanding of their interactions and how they have evolved. I outline a classification system to describe NMD pathways based on the presence/absence of key NMD factors. These types of NMD pathways exist in multiple different lineages, indicating the plasticity of the NMD pathway through recurrent losses of NMD factors during eukaryotic evolution. By classifying the NMD pathways in this way, gaps in our understanding are revealed, even within well studied organisms. Finally, I discuss the likely driving force behind the origins of the NMD pathway before the appearance of the last eukaryotic common ancestor: transposable element expansion and the consequential origin of introns.
10
Echols, Josh, Amna Siddiqui, Yanying Dai, Viktoria Havasi, Richard Sun, Aneta Kaczmarczyk, and Kim M. Keeling. "A regulated NMD mouse model supports NMD inhibition as a viable therapeutic option to treat genetic diseases." Disease Models & Mechanisms 13, no. 8 (July 31, 2020): dmm044891. http://dx.doi.org/10.1242/dmm.044891.
Full textAbstract:
ABSTRACTNonsense-mediated mRNA decay (NMD) targets mRNAs that contain a premature termination codon (PTC) for degradation, preventing their translation. By altering the expression of PTC-containing mRNAs, NMD modulates the inheritance pattern and severity of genetic diseases. NMD also limits the efficiency of suppressing translation termination at PTCs, an emerging therapeutic approach to treat genetic diseases caused by in-frame PTCs (nonsense mutations). Inhibiting NMD may help rescue partial levels of protein expression. However, it is unclear whether long-term, global NMD attenuation is safe. We hypothesize that a degree of NMD inhibition can be safely tolerated after completion of prenatal development. To test this hypothesis, we generated a novel transgenic mouse that expresses an inducible, dominant-negative form of human UPF1 (dnUPF1) to inhibit NMD in mouse tissues by different degrees, allowing us to examine the effects of global NMD inhibition in vivo. A thorough characterization of these mice indicated that expressing dnUPF1 at levels that promote relatively moderate to strong NMD inhibition in most tissues for a 1-month period produced modest immunological and bone alterations. In contrast, 1 month of dnUPF1 expression to promote more modest NMD inhibition in most tissues did not produce any discernable defects, indicating that moderate global NMD attenuation is generally well tolerated in non-neurological somatic tissues. Importantly, a modest level of NMD inhibition that produced no overt abnormalities was able to significantly enhance in vivo PTC suppression. These results suggest that safe levels of NMD attenuation are likely achievable, and this can help rescue protein deficiencies resulting from PTCs.
11
Sulkowska, Aleksandra, Andor Auber, Pawel J. Sikorski, D�niel Silhavy, Mariann Auth, Ewa Sitkiewicz, Viviane Jean, R�my Merret, C�cile Bousquet-Antonelli, and Joanna Kufel. "RNA Helicases from the DEA(D/H)-Box Family Contribute to Plant NMD Efficiency." Plant and Cell Physiology 61, no. 1 (September 27, 2019): 144–57. http://dx.doi.org/10.1093/pcp/pcz186.
Full textAbstract:
Abstract Nonsense-mediated mRNA decay (NMD) is a conserved eukaryotic RNA surveillance mechanism that degrades aberrant mRNAs comprising a premature translation termination codon. The adenosine triphosphate (ATP)-dependent RNA helicase up-frameshift 1 (UPF1) is a major NMD factor in all studied organisms; however, the complexity of this mechanism has not been fully characterized in plants. To identify plant NMD factors, we analyzed UPF1-interacting proteins using tandem affinity purification coupled to mass spectrometry. Canonical members of the NMD pathway were found along with numerous NMD candidate factors, including conserved DEA(D/H)-box RNA helicase homologs of human DDX3, DDX5 and DDX6, translation initiation factors, ribosomal proteins and transport factors. Our functional studies revealed that depletion of DDX3 helicases enhances the accumulation of NMD target reporter mRNAs but does not result in increased protein levels. In contrast, silencing of DDX6 group leads to decreased accumulation of the NMD substrate. The inhibitory effect of DDX6-like helicases on NMD was confirmed by transient overexpression of RH12 helicase. These results indicate that DDX3 and DDX6 helicases in plants have a direct and opposing contribution to NMD and act as functional NMD factors.
12
Patel, Shanila Fernandez, Roberto Vendramin, Danwen Qian, Yue Zhao, Lorena Ligammari, Krupa Thakkar, Jun Murai, Eva Grönroos, Jeremy Carlton, and Kevin Litchfield. "Abstract 5625: Targeting the nonsense mediated mRNA decay pathway to prevent the degradation of highly immunogenic frameshift mutated transcripts." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5625. http://dx.doi.org/10.1158/1538-7445.am2024-5625.
Full textAbstract:
Abstract Introduction: Frameshift insertions/deletions (fs-indels) can lead to the generation of immunogenic non-self-peptides which contribute to anti-tumor immune responses. However, fs-indels often generate premature termination codons (PTCs), leading to mRNA degradation by the nonsense mediated mRNA decay (NMD) pathway. Importantly, some PTC-containing transcripts naturally escape NMD degradation and produce highly immunogenic neoantigens. Therefore, we hypothesize that NMD inhibition could be used to increase the cellular pool of fs-indels derived neoantigens in cancer cells, and enhance anti-tumor immunogenicity. NMD also regulates other cellular processes by degrading a subset of non-PTC-containing self-transcripts. Therefore, by focusing NMD inhibition towards the degradation of PTC-transcripts only, toxicity may be limited in a clinical setting. We investigate how targeting different NMD proteins affects the degradation of fs-transcripts across several cancers types. To assess the clinical relevance of NMD inhibition, we study how it specifically affects p53 fs-transcripts, since p53 is the most mutated gene in cancer and fs-mutant p53 has been shown to be highly immunogenic. Methods: Core NMD proteins were depleted across a panel of cell lines from different cancer types and transcriptomics, flow cytometry, qPCR and western blot were used to evaluate changes in the expression of NMD-targeted transcripts and NMD members. Proteomics and immunopeptidomics were used to study protein expression and HLA-peptide presentation arising from fs-transcripts. A Translating RNA Imaging by Coat protein Knock-off (TRICK) assay was developed to study the translation of NMD-targeted p53 mutants upon NMD inhibition. This assay can precisely quantify the translation of p53 mutant RNA upon different treatments and cellular stresses at single-molecule resolution. Results: We found an increase in expression of PTC-transcripts upon silencing of multiple NMD members. Our data suggests that some NMD members are better targets for inhibition of NMD PTC-surveillance, whilst others are more appropriate for inhibition of NMD-mediated gene expression regulation. These data support the recently proposed hypothesis that NMD is a branched pathway, where each branch targets specific subsets of transcripts depending on the cell type. These results are clinically relevant as the method by which NMD is inhibited could help optimize the generation of immunogenic neoantigens whilst minimizing toxicity. The TRICK assay has shown that inhibiting NMD surveillance reduces the degradation of p53 fs-transcripts and increases their protein expression. Conclusion: We have identified NMD pathway members that can be targeted to efficiently inhibit the surveillance role of NMD and prevent the degradation of fs-transcripts that could generate highly immunogenic neoantigens. Citation Format: Shanila Fernandez Patel, Roberto Vendramin, Danwen Qian, Yue Zhao, Lorena Ligammari, Krupa Thakkar, Jun Murai, Eva Grönroos, Jeremy Carlton, Kevin Litchfield. Targeting the nonsense mediated mRNA decay pathway to prevent the degradation of highly immunogenic frameshift mutated transcripts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5625.
13
Gardner, Lawrence B. "Hypoxic Inhibition of Nonsense-Mediated RNA Decay Regulates Gene Expression and the Integrated Stress Response." Molecular and Cellular Biology 28, no. 11 (March 24, 2008): 3729–41. http://dx.doi.org/10.1128/mcb.02284-07.
Full textAbstract:
ABSTRACT Nonsense-mediated RNA decay (NMD) rapidly degrades both mutated mRNAs and nonmutated cellular mRNAs in what is thought to be a constitutive fashion. Here we demonstrate that NMD is inhibited in hypoxic cells and that this inhibition is dependent on phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). eIF2α phosphorylation is known to promote translational and transcriptional up-regulation of genes important for the cellular response to stress. We show that the mRNAs of several of these stress-induced genes are NMD targets and that the repression of NMD stabilizes these mRNAs, thus demonstrating that the inhibition of NMD augments the cellular stress response. Furthermore, hypoxia-induced formation of cytoplasmic stress granules is also dependent on eIF2α phosphorylation, and components of the NMD pathway are relocalized to these granules in hypoxic cells, providing a potential mechanism for the hypoxic inhibition of NMD. Our demonstration that NMD is inhibited in hypoxic cells reveals that the regulation of NMD can dynamically alter gene expression and also establishes a novel mechanism for hypoxic gene regulation.
14
Becker, Lena-Luise, Hormos Salimi Dafsari, Jens Schallner, Dalia Abdin, Michael Seifert, Florence Petit, Thomas Smol, et al. "The clinical-phenotype continuum in DYNC1H1-related disorders—genomic profiling and proposal for a novel classification." Journal of Human Genetics 65, no. 11 (August 12, 2020): 1003–17. http://dx.doi.org/10.1038/s10038-020-0803-1.
Full textAbstract:
AbstractMutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenic DYNC1H1 variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation of DYNC1H1. We identified ten patients with nine novel mutations in the DYNC1H1 gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation in DYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype–phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength in DYNC1H1–NMD and motor domain with cerebral malformations in DYNC1H1–NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up of DYNC1H1-related disorders. We propose a novel clinical classification for DYNC1H1-related disorders encompassing a spectrum from DYNC1H1–NMD with an exclusive PNS phenotype to DYNC1H1–NDD with concomitant CNS involvement.
15
Wittmann, Jürgen, Elly M. Hol, and Hans-Martin Jäck. "hUPF2 Silencing Identifies Physiologic Substrates of Mammalian Nonsense-Mediated mRNA Decay." Molecular and Cellular Biology 26, no. 4 (February 15, 2006): 1272–87. http://dx.doi.org/10.1128/mcb.26.4.1272-1287.2006.
Full textAbstract:
ABSTRACT Nonsense-mediated mRNA decay (NMD) is a conserved eukaryotic surveillance pathway that selectively degrades aberrant mRNAs with premature termination codons (PTCs). Although a small number of cases exist in mammals, where NMD controls levels of physiologic PTC transcripts, it is still unclear whether the engagement of NMD in posttranscriptional control of gene expression is a more prevalent phenomenon. To identify physiologic NMD substrates and to study how NMD silencing affects the overall dynamics of a cell, we stably down-regulated hUPF2, the human homolog of the yeast NMD factor UPF2, by RNA interference. As expected, hUPF2-silenced HeLa cells were impaired in their ability to recognize ectopically expressed aberrant PTC transcripts. Surprisingly, hUPF2 silencing did not affect cell growth and viability but clearly diminished phosphorylation of hUPF1, suggesting a role of hUPF2 in modulating NMD activity through phosphorylation of hUPF1. Genome-wide DNA microarray expression profiling identified 37 novel up-regulated and 57 down-regulated transcripts in hUPF2-silenced cells. About 60% of the up-regulated mRNAs carry typical NMD motifs. Hence, NMD is important not only for maintaining the transcriptome integrity by removing nonfunctional and aberrant PTC-bearing transcripts but also for posttranscriptional control of selected physiologic transcripts with NMD features.
16
Taylor, Rachel, Bessie Wanja Kebaara, Tara Nazarenus, Ashley Jones, Rena Yamanaka, Rachel Uhrenholdt, Jason P. Wendler, and Audrey L. Atkin. "Gene Set Coregulated by the Saccharomyces cerevisiae Nonsense-Mediated mRNA Decay Pathway." Eukaryotic Cell 4, no. 12 (December 2005): 2066–77. http://dx.doi.org/10.1128/ec.4.12.2066-2077.2005.
Full textAbstract:
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.
17
Durand, Sébastien, Nicolas Cougot, Florence Mahuteau-Betzer, Chi-Hung Nguyen, David S. Grierson, Edouard Bertrand, Jamal Tazi, and Fabrice Lejeune. "Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies." Journal of Cell Biology 178, no. 7 (September 24, 2007): 1145–60. http://dx.doi.org/10.1083/jcb.200611086.
Full textAbstract:
In mammals, nonsense-mediated mRNA decay (NMD) is a quality-control mechanism that degrades mRNA harboring a premature termination codon to prevent the synthesis of truncated proteins. To gain insight into the NMD mechanism, we identified NMD inhibitor 1 (NMDI 1) as a small molecule inhibitor of the NMD pathway. We characterized the mode of action of this compound and demonstrated that it acts upstream of hUPF1. NMDI 1 induced the loss of interactions between hSMG5 and hUPF1 and the stabilization of hyperphosphorylated isoforms of hUPF1. Incubation of cells with NMDI 1 allowed us to demonstrate that NMD factors and mRNAs subject to NMD transit through processing bodies (P-bodies), as is the case in yeast. The results suggest a model in which mRNA and NMD factors are sequentially recruited to P-bodies.
18
Kesarwani, Anil K., Hsin-Chieh Lee, Patrizia G. Ricca, Gabriele Sullivan, Natalie Faiss, Gabriele Wagner, Anna Wunderling, and Andreas Wachter. "Multifactorial and Species-Specific Feedback Regulation of the RNA Surveillance Pathway Nonsense-Mediated Decay in Plants." Plant and Cell Physiology 60, no. 9 (August 1, 2019): 1986–99. http://dx.doi.org/10.1093/pcp/pcz141.
Full textAbstract:
Abstract Nonsense-mediated decay (NMD) is an RNA surveillance mechanism that detects aberrant transcript features and triggers degradation of erroneous as well as physiological RNAs. Originally considered to be constitutive, NMD is now recognized to be tightly controlled in response to inherent signals and diverse stresses. To gain a better understanding of NMD regulation and its functional implications, we systematically examined feedback control of the central NMD components in two dicot and one monocot species. On the basis of the analysis of transcript features, turnover rates and steady-state levels, up-frameshift (UPF) 1, UPF3 and suppressor of morphological defects on genitalia (SMG) 7, but not UPF2, are under feedback control in both dicots. In the monocot investigated in this study, only SMG7 was slightly induced upon NMD inhibition. The detection of the endogenous NMD factor proteins in Arabidopsis thaliana substantiated a negative correlation between NMD activity and SMG7 amounts. Furthermore, evidence was provided that SMG7 is required for the dephosphorylation of UPF1. Our comprehensive and comparative study of NMD feedback control in plants reveals complex and species-specific attenuation of this RNA surveillance pathway, with critical implications for the numerous functions of NMD in physiology and stress responses.
19
Danckwardt, Sven, Gabriele Neu-Yilik, Rolf Thermann, Ute Frede, Matthias W. Hentze, and Andreas E. Kulozik. "Abnormally spliced β-globin mRNAs: a single point mutation generates transcripts sensitive and insensitive to nonsense-mediated mRNA decay." Blood 99, no. 5 (March 1, 2002): 1811–16. http://dx.doi.org/10.1182/blood.v99.5.1811.
Full textAbstract:
Nonsense-mediated mRNA decay (NMD) represents a phylogenetically widely conserved splicing- and translation-dependent mechanism that eliminates transcripts with premature translation stop codons and suppresses the accumulation of C-terminally truncated peptides. Elimination of frameshifted transcripts that result from faulty splicing may be an important function of NMD. To test this hypothesis directly, this study used the IVS1 + 5 G>A thalassemia mutation of the human β-globin gene as a model system. We generated β-globin gene constructs with this mutation and an iron-responsive element in the 5′ untranslated region, which allowed specific experimental activation and inactivation of translation and, hence, NMD of this transcript. Premessenger RNAs with IVS1 + 5 G>A were spliced at normal sites and cryptic sites, enabling a direct comparison of the effect of NMD on the accumulation of normal and frameshifted messenger RNAs. In transfected HeLa cells, the predominant frameshifted transcript was degraded under conditions of active NMD, whereas accumulation to high levels occurred under conditions of specifically disabled NMD, thereby indicating an important physiologic function of NMD in the control of the splicing process. An unexpected finding was that accumulation of a second aberrant transcript remained unaffected by NMD. The IVS1 + 5 G>A mutation thus revealed the presence of an unknown cis-acting determinant that influences the NMD sensitivity of a putative NMD substrate. It can therefore serve as a useful tool for defining the mechanisms that permit specific transcripts to circumvent the NMD pathway.
20
Andjus, Sara, Antonin Morillon, and Maxime Wery. "From Yeast to Mammals, the Nonsense-Mediated mRNA Decay as a Master Regulator of Long Non-Coding RNAs Functional Trajectory." Non-Coding RNA 7, no. 3 (July 27, 2021): 44. http://dx.doi.org/10.3390/ncrna7030044.
Full textAbstract:
The Nonsense-Mediated mRNA Decay (NMD) has been classically viewed as a translation-dependent RNA surveillance pathway degrading aberrant mRNAs containing premature stop codons. However, it is now clear that mRNA quality control represents only one face of the multiple functions of NMD. Indeed, NMD also regulates the physiological expression of normal mRNAs, and more surprisingly, of long non-coding (lnc)RNAs. Here, we review the different mechanisms of NMD activation in yeast and mammals, and we discuss the molecular bases of the NMD sensitivity of lncRNAs, considering the functional roles of NMD and of translation in the metabolism of these transcripts. In this regard, we describe several examples of functional micropeptides produced from lncRNAs. We propose that translation and NMD provide potent means to regulate the expression of lncRNAs, which might be critical for the cell to respond to environmental changes.
21
Vicente-Crespo, Marta, and Isabel M. Palacios. "Nonsense-mediated mRNA decay and development: shoot the messenger to survive?" Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1500–1505. http://dx.doi.org/10.1042/bst0381500.
Full textAbstract:
NMD (nonsense-mediated mRNA decay) is a surveillance mechanism that degrades transcripts containing nonsense mutations, preventing the translation of potentially harmful truncated proteins. Although the mechanistic details of NMD are gradually being understood, the physiological role of this RNA surveillance pathway still remains largely unknown. The core NMD genes Upf1 (up-frameshift suppressor 1) and Upf2 are essential for animal viability in the fruitfly, mouse and zebrafish. These findings may reflect an important role for NMD during animal development. Alternatively, the lethal phenotypes of upf1 and upf2 mutants might be due to their function in NMD-independent processes. In the present paper, we describe the phenotypes observed when the NMD factors are mutated in various organisms, and discuss findings that might shed light on the function of NMD in cellular growth and development of an organism.
22
Pawlicka, Kamila, Umesh Kalathiya, and Javier Alfaro. "Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics." Cancers 12, no. 3 (March 24, 2020): 765. http://dx.doi.org/10.3390/cancers12030765.
Full textAbstract:
Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a surveillance pathway used by cells to control the quality mRNAs and to fine-tune transcript abundance. NMD plays an important role in cell cycle regulation, cell viability, DNA damage response, while also serving as a barrier to virus infection. Disturbance of this control mechanism caused by genetic mutations or dys-regulation of the NMD pathway can lead to pathologies, including neurological disorders, immune diseases and cancers. The role of NMD in cancer development is complex, acting as both a promoter and a barrier to tumour progression. Cancer cells can exploit NMD for the downregulation of key tumour suppressor genes, or tumours adjust NMD activity to adapt to an aggressive immune microenvironment. The latter case might provide an avenue for therapeutic intervention as NMD inhibition has been shown to lead to the production of neoantigens that stimulate an immune system attack on tumours. For this reason, understanding the biology and co-option pathways of NMD is important for the development of novel therapeutic agents. Inhibitors, whose design can make use of the many structures available for NMD study, will play a crucial role in characterizing and providing diverse therapeutic options for this pathway in cancer and other diseases.
23
Nagar, Preeti, Md Rafikul Islam, and Mohammad Alinoor Rahman. "Nonsense-Mediated mRNA Decay as a Mediator of Tumorigenesis." Genes 14, no. 2 (January 30, 2023): 357. http://dx.doi.org/10.3390/genes14020357.
Full textAbstract:
Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved and well-characterized biological mechanism that ensures the fidelity and regulation of gene expression. Initially, NMD was described as a cellular surveillance or quality control process to promote selective recognition and rapid degradation of erroneous transcripts harboring a premature translation-termination codon (PTC). As estimated, one-third of mutated and disease-causing mRNAs were reported to be targeted and degraded by NMD, suggesting the significance of this intricate mechanism in maintaining cellular integrity. It was later revealed that NMD also elicits down-regulation of many endogenous mRNAs without mutations (~10% of the human transcriptome). Therefore, NMD modulates gene expression to evade the generation of aberrant truncated proteins with detrimental functions, compromised activities, or dominant-negative effects, as well as by controlling the abundance of endogenous mRNAs. By regulating gene expression, NMD promotes diverse biological functions during development and differentiation, and facilitates cellular responses to adaptation, physiological changes, stresses, environmental insults, etc. Mutations or alterations (such as abnormal expression, degradation, post-translational modification, etc.) that impair the function or expression of proteins associated with the NMD pathway can be deleterious to cells and may cause pathological consequences, as implicated in developmental and intellectual disabilities, genetic defects, and cancer. Growing evidence in past decades has highlighted NMD as a critical driver of tumorigenesis. Advances in sequencing technologies provided the opportunity to identify many NMD substrate mRNAs in tumor samples compared to matched normal tissues. Interestingly, many of these changes are tumor-specific and are often fine-tuned in a tumor-specific manner, suggesting the complex regulation of NMD in cancer. Tumor cells differentially exploit NMD for survival benefits. Some tumors promote NMD to degrade a subset of mRNAs, such as those encoding tumor suppressors, stress response proteins, signaling proteins, RNA binding proteins, splicing factors, and immunogenic neoantigens. In contrast, some tumors suppress NMD to facilitate the expression of oncoproteins or other proteins beneficial for tumor growth and progression. In this review, we discuss how NMD is regulated as a critical mediator of oncogenesis to promote the development and progression of tumor cells. Understanding how NMD affects tumorigenesis differentially will pave the way for the development of more effective and less toxic, targeted therapeutic opportunities in the era of personalized medicine.
24
Lejeune, Fabrice. "Nonsense-Mediated mRNA Decay, a Finely Regulated Mechanism." Biomedicines 10, no. 1 (January 10, 2022): 141. http://dx.doi.org/10.3390/biomedicines10010141.
Full textAbstract:
Nonsense-mediated mRNA decay (NMD) is both a mechanism for rapidly eliminating mRNAs carrying a premature termination codon and a pathway that regulates many genes. This implies that NMD must be subject to regulation in order to allow, under certain physiological conditions, the expression of genes that are normally repressed by NMD. Therapeutically, it might be interesting to express certain NMD-repressed genes or to allow the synthesis of functional truncated proteins. Developing such approaches will require a good understanding of NMD regulation. This review describes the different levels of this regulation in human cells.
25
Amrani, N., S. Dong, F. He, R. Ganesan, S. Ghosh, S. Kervestin, C. Li, D. A. Mangus, P. Spatrick, and A. Jacobson. "Aberrant termination triggers nonsense-mediated mRNA decay." Biochemical Society Transactions 34, no. 1 (January 20, 2006): 39–42. http://dx.doi.org/10.1042/bst0340039.
Full textAbstract:
NMD (nonsense-mediated mRNA decay) is a cellular quality-control mechanism in which an otherwise stable mRNA is destabilized by the presence of a premature termination codon. We have defined the set of endogenous NMD substrates, demonstrated that they are available for NMD at every round of translation, and showed that premature termination and normal termination are not equivalent biochemical events. Premature termination is aberrant, and its NMD-stimulating defects can be reversed by the presence of tethered poly(A)-binding protein (Pab1p) or tethered eRF3 (eukaryotic release factor 3) (Sup35p). Thus NMD appears to be triggered by a ribosome's failure to terminate adjacent to a properly configured 3′-UTR (untranslated region), an event that may promote binding of the UPF/NMD factors to stimulate mRNA decapping.
26
Guo, Yanwu, Cristina Tocchini, and Rafal Ciosk. "CLK-2/TEL2 is a conserved component of the nonsense-mediated mRNA decay pathway." PLOS ONE 16, no. 1 (January 14, 2021): e0244505. http://dx.doi.org/10.1371/journal.pone.0244505.
Full textAbstract:
Nonsense-mediated mRNA decay (NMD) controls eukaryotic mRNA quality, inducing the degradation of faulty transcripts. Key players in the NMD pathway were originally identified, through genetics, in Caenorhabditis elegans as smg (suppressor with morphological effect on genitalia) genes. Using forward genetics and fluorescence-based NMD reporters, we reexamined the genetic landscape underlying NMD. Employing a novel strategy for mapping sterile mutations, Het-Map, we identified clk-2, a conserved gene previously implicated in DNA damage signaling, as a player in the nematode NMD. We find that CLK-2 is expressed predominantly in the germline, highlighting the importance of auxiliary factors in tissue-specific mRNA decay. Importantly, the human counterpart of CLK-2/TEL2, TELO2, has been also implicated in the NMD, suggesting a conserved role of CLK-2/TEL2 proteins in mRNA surveillance. Recently, variants of TELO2 have been linked to an intellectual disability disorder, the You-Hoover-Fong syndrome, which could be related to its function in the NMD.
27
Wang, Weirong, Iván J. Cajigas, Stuart W. Peltz, Miles F. Wilkinson, and Carlos I. González. "Role for Upf2p Phosphorylation in Saccharomyces cerevisiae Nonsense-Mediated mRNA Decay." Molecular and Cellular Biology 26, no. 9 (May 1, 2006): 3390–400. http://dx.doi.org/10.1128/mcb.26.9.3390-3400.2006.
Full textAbstract:
ABSTRACT Premature termination (nonsense) codons trigger rapid mRNA decay by the nonsense-mediated mRNA decay (NMD) pathway. Two conserved proteins essential for NMD, UPF1 and UPF2, are phosphorylated in higher eukaryotes. The phosphorylation and dephosphorylation of UPF1 appear to be crucial for NMD, as blockade of either event in Caenorhabditis elegans and mammals largely prevents NMD. The universality of this phosphorylation/dephosphorylation cycle pathway has been questioned, however, because the well-studied Saccharomyces cerevisiae NMD pathway has not been shown to be regulated by phosphorylation. Here, we used in vitro and in vivo biochemical techniques to show that both S. cerevisiae Upf1p and Upf2p are phosphoproteins. We provide evidence that the phosphorylation of the N-terminal region of Upf2p is crucial for its interaction with Hrp1p, an RNA-binding protein that we previously showed is essential for NMD. We identify specific amino acids in Upf2p's N-terminal domain, including phosphorylated serines, which dictate both its interaction with Hrp1p and its ability to elicit NMD. Our results indicate that phosphorylation of UPF1 and UPF2 is a conserved event in eukaryotes and for the first time provide evidence that Upf2p phosphorylation is crucial for NMD.
28
Ahmed, Md Robel, and Zhiyou Du. "Molecular Interaction of Nonsense-Mediated mRNA Decay with Viruses." Viruses 15, no. 4 (March 23, 2023): 816. http://dx.doi.org/10.3390/v15040816.
Full textAbstract:
The virus–host interaction is dynamic and evolutionary. Viruses have to fight with hosts to establish successful infection. Eukaryotic hosts are equipped with multiple defenses against incoming viruses. One of the host defenses against viruses is the nonsense-mediated mRNA decay (NMD), an evolutionarily conserved mechanism for RNA quality control in eukaryotic cells. NMD ensures the accuracy of mRNA translation by removing the abnormal mRNAs harboring pre-matured stop codons. Many RNA viruses have a genome that contains internal stop codon(s) (iTC). Akin to the premature termination codon in aberrant RNA transcripts, the presence of iTC would activate NMD to degrade iTC-containing viral genomes. A couple of viruses have been reported to be sensitive to the NMD-mediated antiviral defense, while some viruses have evolved with specific cis-acting RNA features or trans-acting viral proteins to overcome or escape from NMD. Recently, increasing light has been shed on the NMD–virus interaction. This review summarizes the current scenario of NMD-mediated viral RNA degradation and classifies various molecular means by which viruses compromise the NMD-mediated antiviral defense for better infection in their hosts.
29
García-Moreno, Juan F., and Luísa Romão. "Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay." International Journal of Molecular Sciences 21, no. 24 (December 10, 2020): 9424. http://dx.doi.org/10.3390/ijms21249424.
Full textAbstract:
Alternative splicing (AS) of precursor mRNA (pre-mRNA) is a cellular post-transcriptional process that generates protein isoform diversity. Nonsense-mediated RNA decay (NMD) is an mRNA surveillance pathway that recognizes and selectively degrades transcripts containing premature translation-termination codons (PTCs), thereby preventing the production of truncated proteins. Nevertheless, NMD also fine-tunes the gene expression of physiological mRNAs encoding full-length proteins. Interestingly, around one third of all AS events results in PTC-containing transcripts that undergo NMD. Numerous studies have reported a coordinated action between AS and NMD, in order to regulate the expression of several genes, especially those coding for RNA-binding proteins (RBPs). This coupling of AS to NMD (AS-NMD) is considered a gene expression tool that controls the ratio of productive to unproductive mRNA isoforms, ultimately degrading PTC-containing non-functional mRNAs. In this review, we focus on the mechanisms underlying AS-NMD, and how this regulatory process is able to control the homeostatic expression of numerous RBPs, including splicing factors, through auto- and cross-regulatory feedback loops. Furthermore, we discuss the importance of AS-NMD in the regulation of biological processes, such as cell differentiation. Finally, we analyze interesting recent data on the relevance of AS-NMD to human health, covering its potential roles in cancer and other disorders.
30
Nakano, Kazumi, Nobuaki Karasawa, Masaaki Hashizume, Yuetsu Tanaka, Takeo Ohsugi, Kaoru Uchimaru, and Toshiki Watanabe. "Elucidation of the Mechanism of Host NMD Suppression by HTLV-1 Rex: Dissection of Rex to Identify the NMD Inhibitory Domain." Viruses 14, no. 2 (February 9, 2022): 344. http://dx.doi.org/10.3390/v14020344.
Full textAbstract:
The human retrovirus human T-cell leukemia virus type I (HTLV-1) infects human T cells by vertical transmission from mother to child through breast milk or horizontal transmission through blood transfusion or sexual contact. Approximately 5% of infected individuals develop adult T-cell leukemia/lymphoma (ATL) with a poor prognosis, while 95% of infected individuals remain asymptomatic for the rest of their lives, during which time the infected cells maintain a stable immortalized latent state in the body. It is not known why such a long latent state is maintained. We hypothesize that the role of functional proteins of HTLV-1 during early infection influences the phenotype of infected cells in latency. In eukaryotic cells, a mRNA quality control mechanism called nonsense-mediated mRNA decay (NMD) functions not only to eliminate abnormal mRNAs with nonsense codons but also to target virus-derived RNAs. We have reported that HTLV-1 genomic RNA is a potential target of NMD, and that Rex suppresses NMD and stabilizes viral RNA against it. In this study, we aimed to elucidate the molecular mechanism of NMD suppression by Rex using various Rex mutant proteins. We found that region X (aa20–57) of Rex, the function of which has not been clarified, is required for NMD repression. We showed that Rex binds to Upf1, which is the host key regulator to detect abnormal mRNA and initiate NMD, through this region. Rex also interacts with SMG5 and SMG7, which play essential roles for the completion of the NMD pathway. Moreover, Rex selectively binds to Upf3B, which is involved in the normal NMD complex, and replaces it with a less active form, Upf3A, to reduce NMD activity. These results revealed that Rex invades the NMD cascade from its initiation to completion and suppresses host NMD activity to protect the viral genomic mRNA.
31
Barbier, Jérôme, Martin Dutertre, Danielle Bittencourt, Gabriel Sanchez, Lise Gratadou, Pierre de la Grange, and Didier Auboeuf. "Regulation of H-ras Splice Variant Expression by Cross Talk between the p53 and Nonsense-Mediated mRNA Decay Pathways." Molecular and Cellular Biology 27, no. 20 (August 20, 2007): 7315–33. http://dx.doi.org/10.1128/mcb.00272-07.
Full textAbstract:
ABSTRACT When cells are exposed to a genotoxic stress, a DNA surveillance pathway that involves p53 is activated, allowing DNA repair. Eukaryotic cells have also evolved a mechanism called mRNA surveillance that controls the quality of mRNAs. Indeed, mutant mRNAs carrying premature translation termination codons (PTCs) are selectively degraded by the nonsense-mediated mRNA decay (NMD) pathway. However, in the case of particular genes, such as proto-oncogenes, mutations that do not create PTCs and therefore that do not induce mRNA degradation, can be harmful to cells. In this study, we showed that the H-ras gene in the absence of mutations produces an NMD-target splice variant that is degraded in the cytosol. We observed that a treatment with the genotoxic stress inducer camptothecin for 6 h favored the production of the H-ras NMD-target transcript degraded in the cytosol by the NMD process. Our data indicated that the NMD process allowed the elimination of transcripts produced in response to a short-term treatment with camptothecin from the major proto-oncogene H-ras, independently of PTCs induced by mutations. The camptothecin effects on H-ras gene expression were p53 dependent and involved in part modulation of the SC35 splicing factor. Interestingly, a long-term treatment with camptothecin as well as p53 overexpression for 24 h resulted in the accumulation of the H-ras NMD target in the cytosol, although the NMD process was not completely inhibited as other NMD targets are not stabilized. Finally, Upf1, a major NMD effector, was necessary for optimal p53 activation by camptothecin, which is consistent with recent data showing that NMD effectors are required for genome stability. In conclusion, we identified cross talk between the p53 and NMD pathways that regulates the expression levels of H-ras splice variants.
32
Gardner, Lawrence B. "Inhibition of Nonsense Mediated RNA Decay in Hypoxic Cells; Implications for Thalassemia." Blood 110, no. 11 (November 16, 2007): 1781. http://dx.doi.org/10.1182/blood.v110.11.1781.1781.
Full textAbstract:
Abstract Several common β globin gene mutations found in thalassemia are thought to promote rapid degradation of the aberrant mRNA through a specific mechanism termed nonsense mediated RNA decay (NMD). NMD, elicited through mutations leading to premature termination codons, is thought to be responsible not only for the degradation of the β globin PTC 39 mutation, responsible for >90% of thalassemia in Sardinia, but also for the degradation of 30% of all known human mutations and up to 10% of the genome. However, because NMD has been thought of as a constitutive and not a regulated pathway, the potential role of NMD in the dynamic regulation of gene expression has not been well explored. We have determined that NMD is inhibited in hypoxic cells. This hypoxic inhibition of NMD significantly prolongs the half-life of multiple mRNAs degraded by NMD, including the β globin PTC 39 mutation. We have also identified several additional mRNAs whose stabilities are significantly (>2 fold) 1. Increased when Rent1, an RNA helicase necessary for NMD is silenced 2. Decreased when Rent1 is over-expressed and 3. Increased in hypoxic cells when NMD is inhibited. These include the mRNAs that are integral for the cellular response to multiple stresses found in thalassemia, including hypoxic stress. Indeed, we observed that the cellular stress response is augmented when NMD is inhibited. The central component for many cellular stress responses is the phosphorylation of a translation factor, eIF2α. We and others have demonstrated that eIF2α is phosphorylated in hypoxic cells via the kinase PERK. Phosphorylation of eIF2α leads to the suppression of protein synthesis and the translational and transcriptional up-regulation of stress response genes. We hypothesized that phosphorylation of eIF2α was also responsible for the hypoxic inhibition of NMD. Indeed, when we used cells generated from mice in which wild-type eIF2α has been replaced by an eIF2α that cannot be phosphorylated, we found that hypoxic inhibition of NMD did not occur, demonstrating that is eIF2α phosphorylation is necessary for hypoxic inhibition of NMD. Degradation of NMD targets occurs in cytoplasmic processing bodies, which contain many of the enzymes necessary for mRNA catabolism. We noted that a distinct type of mRNA containing body, termed stress bodies, which do not have the capacity for RNA decay, are induced in hypoxic cells. This formation is dependent on PERK phosphorylation of eIF2α. While there are several potential mechanism by which hypoxic phosphorylation of eIF2α could inhibit NMD, our preliminary data suggests a model in which NMD targets are sequestered in cytoplasmic stress granules in hypoxic cells, thus excluding them from cytoplasmic processing bodies. Thus our studies reveal a novel form of gene regulation in hypoxic cells, regulation of NMD via phosphorylation of eIF2α. This finding has potential significance in many disease states, but particularly in thalassemia, where many of the stresses which phosphorylate eIF2α occur, and where the stress response and regulation of mutated β globin mRNAs may be particularly important.
33
Lee, Paul Jongseo, Suzhou Yang, Yu Sun, and Junjie U. Guo. "Regulation of nonsense-mediated mRNA decay in neural development and disease." Journal of Molecular Cell Biology 13, no. 4 (March 30, 2021): 269–81. http://dx.doi.org/10.1093/jmcb/mjab022.
Full textAbstract:
Abstract Eukaryotes have evolved a variety of mRNA surveillance mechanisms to detect and degrade aberrant mRNAs with potential deleterious outcomes. Among them, nonsense-mediated mRNA decay (NMD) functions not only as a quality control mechanism targeting aberrant mRNAs containing a premature termination codon but also as a posttranscriptional gene regulation mechanism targeting numerous physiological mRNAs. Despite its well-characterized molecular basis, the regulatory scope and biological functions of NMD at an organismal level are incompletely understood. In humans, mutations in genes encoding core NMD factors cause specific developmental and neurological syndromes, suggesting a critical role of NMD in the central nervous system. Here, we review the accumulating biochemical and genetic evidence on the developmental regulation and physiological functions of NMD as well as an emerging role of NMD dysregulation in neurodegenerative diseases.
34
Lavysh, Daria, and Gabriele Neu-Yilik. "UPF1-Mediated RNA Decay—Danse Macabre in a Cloud." Biomolecules 10, no. 7 (July 4, 2020): 999. http://dx.doi.org/10.3390/biom10070999.
Full textAbstract:
Nonsense-mediated RNA decay (NMD) is the prototype example of a whole family of RNA decay pathways that unfold around a common central effector protein called UPF1. While NMD in yeast appears to be a linear pathway, NMD in higher eukaryotes is a multifaceted phenomenon with high variability with respect to substrate RNAs, degradation efficiency, effector proteins and decay-triggering RNA features. Despite increasing knowledge of the mechanistic details, it seems ever more difficult to define NMD and to clearly distinguish it from a growing list of other UPF1-mediated RNA decay pathways (UMDs). With a focus on mammalian NMD, we here critically examine the prevailing NMD models and the gaps and inconsistencies in these models. By exploring the minimal requirements for NMD and other UMDs, we try to elucidate whether they are separate and definable pathways, or rather variations of the same phenomenon. Finally, we suggest that the operating principle of the UPF1-mediated decay family could be considered similar to that of a computing cloud providing a flexible infrastructure with rapid elasticity and dynamic access according to specific user needs.
35
Raimondeau, Etienne, Joshua C. Bufton, and Christiane Schaffitzel. "New insights into the interplay between the translation machinery and nonsense-mediated mRNA decay factors." Biochemical Society Transactions 46, no. 3 (April 6, 2018): 503–12. http://dx.doi.org/10.1042/bst20170427.
Full textAbstract:
Faulty mRNAs with a premature stop codon (PTC) are recognized and degraded by nonsense-mediated mRNA decay (NMD). Recognition of a nonsense mRNA depends on translation and on the presence of NMD-enhancing or the absence of NMD-inhibiting factors in the 3′-untranslated region. Our review summarizes our current understanding of the molecular function of the conserved NMD factors UPF3B and UPF1, and of the anti-NMD factor Poly(A)-binding protein, and their interactions with ribosomes translating PTC-containing mRNAs. Our recent discovery that UPF3B interferes with human translation termination and enhances ribosome dissociation in vitro, whereas UPF1 is inactive in these assays, suggests a re-interpretation of previous experiments and modification of prevalent NMD models. Moreover, we discuss recent work suggesting new functions of the key NMD factor UPF1 in ribosome recycling, inhibition of translation re-initiation and nascent chain ubiquitylation. These new findings suggest that the interplay of UPF proteins with the translation machinery is more intricate than previously appreciated, and that this interplay quality-controls the efficiency of termination, ribosome recycling and translation re-initiation.
36
Carey, Iain M., Niranjanan Nirmalananthan, Tess Harris, Stephen DeWilde, Umar A. R. Chaudhry, Elizabeth Limb, and Derek G. Cook. "Prevalence of co-morbidity and history of recent infection in patients with neuromuscular disease: A cross-sectional analysis of United Kingdom primary care data." PLOS ONE 18, no. 3 (March 1, 2023): e0282513. http://dx.doi.org/10.1371/journal.pone.0282513.
Full textAbstract:
Background People with neuromuscular disease (NMD) experience a broader range of chronic diseases and health symptoms compared to the general population. However, no comprehensive analysis has directly quantified this to our knowledge. Methods We used a large UK primary care database (Clinical Practice Research Datalink) to compare the prevalence of chronic diseases and other health conditions, including recent infections between 23,876 patients with NMD ever recorded by 2019 compared to 95,295 age-sex-practice matched patients without NMD. Modified Poisson regression estimated Prevalence Ratios (PR) to summarise the presence of the disease/condition ever (or for infections in 2018) in NMD patients versus non-NMD patients. Results Patients with NMD had significantly higher rates for 16 of the 18 conditions routinely recorded in the primary care Quality and Outcomes Framework (QOF). Approximately 1-in-10 adults with NMD had ≥4 conditions recorded (PR = 1.39, 95%CI 1.33–1.45). Disparities were more pronounced at younger ages (18–49). For other (non-QOF) health conditions, significantly higher recorded levels were observed for rarer events (pulmonary embolism PR = 1.96 95%CI 1.76–2.18, hip fractures PR = 1.65 95%CI 1.47–1.85) as well as for more common primary care conditions (constipation PR = 1.52 95%CI 1.46–1.57, incontinence PR = 1.52 95%CI 1.44–1.60). The greatest co-morbidity burden was in patients with a myotonic disorder. Approximately 1-in-6 (17.1%) NMD patients had an infection recorded in the preceding year, with the risk of being hospitalised with an infection nearly double (PR = 1.92, 95%CI 1.79–2.07) compared to non-NMD patients. Conclusion The burden of chronic co-morbidity among patients with NMD is extremely high compared to the general population, and they are also more likely to present in primary and secondary care for acute events such as infections.
37
Carrard, Julie, Fiona Ratajczak, Joséphine Elsens, Catherine Leroy, Rebekah Kong, Lucie Geoffroy, Arnaud Comte, et al. "Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System." Biomedicines 11, no. 10 (October 16, 2023): 2801. http://dx.doi.org/10.3390/biomedicines11102801.
Full textAbstract:
Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that degrades mRNAs carrying a premature termination codon. Its inhibition, alone or in combination with other approaches, could be exploited to develop therapies for genetic diseases caused by a nonsense mutation. This, however, requires molecules capable of inhibiting NMD effectively without inducing toxicity. We have built a new screening system and used it to identify and validate two new molecules that can inhibit NMD at least as effectively as cycloheximide, a reference NMD inhibitor molecule. These new NMD inhibitors show no cellular toxicity at tested concentrations and have a working concentration between 6.2 and 12.5 µM. We have further validated this NMD-inhibiting property in a physiopathological model of lung cancer in which the TP53 gene carries a nonsense mutation. These new molecules may potentially be of interest in the development of therapies for genetic diseases caused by a nonsense mutation.
38
Nasim, Zeeshan, Muhammad Fahim, Katarzyna Gawarecka, Hendry Susila, Suhyun Jin, Geummin Youn, and Ji Hoon Ahn. "Role of AT1G72910, AT1G72940, and ADR1-LIKE 2 in Plant Immunity under Nonsense-Mediated mRNA Decay-Compromised Conditions at Low Temperatures." International Journal of Molecular Sciences 21, no. 21 (October 27, 2020): 7986. http://dx.doi.org/10.3390/ijms21217986.
Full textAbstract:
Nonsense-mediated mRNA decay (NMD) removes aberrant transcripts to avoid the accumulation of truncated proteins. NMD regulates nucleotide-binding, leucine-rich repeat (NLR) genes to prevent autoimmunity; however, the function of a large number of NLRs still remains poorly understood. Here, we show that three NLR genes (AT1G72910, AT1G72940, and ADR1-LIKE 2) are important for NMD-mediated regulation of defense signaling at lower temperatures. At 16 °C, the NMD-compromised up-frameshift protein1 (upf1) upf3 mutants showed growth arrest that can be rescued by the artificial miRNA-mediated knockdown of the three NLR genes. mRNA levels of these NLRs are induced by Pseudomonas syringae inoculation and exogenous SA treatment. Mutations in AT1G72910, AT1G72940, and ADR1-LIKE 2 genes resulted in increased susceptibility to Pseudomonas syringae, whereas their overexpression resulted in severely stunted growth, which was dependent on basal disease resistance genes. The NMD-deficient upf1 upf3 mutants accumulated higher levels of NMD signature-containing transcripts from these NLR genes at 16 °C. Furthermore, mRNA degradation kinetics showed that these NMD signature-containing transcripts were more stable in upf1 upf3 mutants. Based on these findings, we propose that AT1G72910, AT1G72940, and ADR1-LIKE 2 are directly regulated by NMD in a temperature-dependent manner and play an important role in modulating plant immunity at lower temperatures.
39
Christle, Jeffrey W., Tina Duong, Dana Parker, Veronica Stevens, Sally Dunaway Young, Beth D. Kaufman, Whitney Tang, et al. "Cardiopulmonary Exercise Testing for Patients With Neuromuscular Disease and Limited Mobility." Journal of Clinical Exercise Physiology 12, no. 1 (March 1, 2023): 12–17. http://dx.doi.org/10.31189/2165-6193-12.1.12.
Full textAbstract:
ABSTRACT Background Patients with neuromuscular disease (NMD) have progressive muscle weakness and limited mobility that contributes to a sedentary lifestyle. A sedentary lifestyle often leads to deconditioning and decreases cardiorespiratory fitness (CRF). Cardiopulmonary exercise testing (CPX) is the gold standard for the evaluation of CRF but has not been widely applied in patients with NMD. Methods Patients with NMD were recruited from the Neuromuscular Clinic at the Stanford Neurosciences Health Center at Stanford University. Matched controls were recruited by staff from the local community by word of mouth. All participants performed CPX using a wheelchair-accessible total body trainer and a wearable metabolic cart system to volitional exhaustion. Results Participants with NMD and limited mobility (n = 37) were able to perform high-quality CPX with no adverse events or safety concerns of comparable quality to controls. Average respiratory exchange ratio for NMD patients was 1.08 ± 0.16, and average rating of perceived exertion was 18 ± 2 compared with 1.16 ± 0.12 and 18 ± 2 for controls, respectively (P = 0.17 and P = 0.78, respectively). Patients with NMD on average showed markedly reduced percent predicted VO2max and impaired ventilatory efficiency. Conclusion High-quality CPX in patients with NMD may reveal distinct physiological profiles that may lead to a better understanding of pathology in these individuals. CPX on total body trainers may be a viable method for improving exercise prescription for patients with NMD.
40
Brogna, Saverio, Preethi Ramanathan, and Jikai Wen. "UPF1 P-body localization." Biochemical Society Transactions 36, no. 4 (July 22, 2008): 698–700. http://dx.doi.org/10.1042/bst0360698.
Full textAbstract:
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.
41
McHugh, Daniel R., Calvin U. Cotton, and Craig A. Hodges. "Synergy between Readthrough and Nonsense Mediated Decay Inhibition in a Murine Model of Cystic Fibrosis Nonsense Mutations." International Journal of Molecular Sciences 22, no. 1 (December 31, 2020): 344. http://dx.doi.org/10.3390/ijms22010344.
Full textAbstract:
Many heritable genetic disorders arise from nonsense mutations, which generate premature termination codons (PTCs) in transcribed mRNA. PTCs ablate protein synthesis by prematurely terminating the translation of mutant mRNA, as well as reducing mutant mRNA quantity through targeted degradation by nonsense-mediated decay (NMD) mechanisms. Therapeutic strategies for nonsense mutations include facilitating ribosomal readthrough of the PTC and/or inhibiting NMD to restore protein function. However, the efficacy of combining readthrough agents and NMD inhibitors has not been thoroughly explored. In this study, we examined combinations of known NMD inhibitors and readthrough agents using functional analysis of the CFTR protein in primary cells from a mouse model carrying a G542X nonsense mutation in Cftr. We observed synergy between an inhibitor of the NMD component SMG-1 (SMG1i) and the readthrough agents G418, gentamicin, and paromomycin, but did not observe synergy with readthrough caused by amikacin, tobramycin, PTC124, escin, or amlexanox. These results indicate that treatment with NMD inhibitors can increase the quantity of functional protein following readthrough, and that combining NMD inhibitors and readthrough agents represents a potential therapeutic option for treating nonsense mutations.
42
Nicholson, Pamela, and Oliver Mühlemann. "Cutting the nonsense: the degradation of PTC-containing mRNAs." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1615–20. http://dx.doi.org/10.1042/bst0381615.
Full textAbstract:
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.
43
Wittkopp, Nadine, Eric Huntzinger, Catrin Weiler, Jérôme Saulière, Steffen Schmidt, Mahendra Sonawane, and Elisa Izaurralde. "Nonsense-Mediated mRNA Decay Effectors Are Essential for Zebrafish Embryonic Development and Survival." Molecular and Cellular Biology 29, no. 13 (May 4, 2009): 3517–28. http://dx.doi.org/10.1128/mcb.00177-09.
Full textAbstract:
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.
44
Wu, Xingxin, Tao Tan, and Qiang Xu. "Metastatic colorectal cancer cells harness nonsense-mediated mRNA decay for immune evasion." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 242.17. http://dx.doi.org/10.4049/jimmunol.204.supp.242.17.
Full textAbstract:
Abstract Immunosuppression microenvironment allows primary tumor growth, while tumor-inherent factors that bring about immune evasion during metastasis remain elusive. Here, we observed a stronger nonsense-mediated mRNA decay (NMD) activity with a higher expression of up-frameshift protein 1 (UPF1) in colorectal cancer (CRC) metastasis than in matched primary cancer cells. In metastatic CRC SW620 cells, the higher UPF1 expression was found to arise from the increased stability of UPF1 by ubiquitin specific peptidase 10 (USP10)-mediated deubiquitination. In contrast, in primary CRC SW480 cells, autophagy promotes proteolysis of ubiquitinated UPF1 and inhibits NMD activity. Interestingly, in SW620 cells NMD selectively controlled a cluster of immune-related genes including ICAM1. Furthermore, NMD inhibition exposed SW620 cells but not SW480 cells to natural killer (NK) cell-mediated cytolysis that depended on ICAM1. Conclusion NMD activity can be recommissioned in CRC metastasis cells to escape from NK-dependent immune surveillance, and inhibiting NMD to boost anti-tumor immunity could be a novel strategy to treat CRC metastasis.
45
Ma, Zhengxin, Ratna Sharma, and Aric N. Rogers. "Physiological Consequences of Nonsense-Mediated Decay and Its Role in Adaptive Responses." Biomedicines 12, no. 5 (May 16, 2024): 1110. http://dx.doi.org/10.3390/biomedicines12051110.
Full textAbstract:
The evolutionarily conserved nonsense-mediated mRNA decay (NMD) pathway is a quality control mechanism that degrades aberrant mRNA containing one or more premature termination codons (PTCs). Recent discoveries indicate that NMD also differentially regulates mRNA from wild-type protein-coding genes despite lacking PTCs. Together with studies showing that NMD is involved in development and adaptive responses that influence health and longevity, these findings point to an expanded role of NMD that adds a new layer of complexity in the post-transcriptional regulation of gene expression. However, the extent of its control, whether different types of NMD play different roles, and the resulting physiological outcomes remain unclear and need further elucidation. Here, we review different branches of NMD and what is known of the physiological outcomes associated with this type of regulation. We identify significant gaps in the understanding of this process and the utility of genetic tools in accelerating progress in this area.
46
Preusse, C., T. Marteau, N. Fischer, A. Hentschel, S. Lang, C. Dittmayer, U. Schneider, et al. "AUTOIMMUNE & INFLAMMATORY NMD." Neuromuscular Disorders 31 (October 2021): S53. http://dx.doi.org/10.1016/j.nmd.2021.07.037.
Full text
47
Yamanaka, A., N. Eura, M. Yamaoka, M. Ozaki, T. Shiota, H. Nanaura, and K. Sugie. "AUTOIMMUNE & INFLAMMATORY NMD." Neuromuscular Disorders 31 (October 2021): S51. http://dx.doi.org/10.1016/j.nmd.2021.07.030.
Full text
48
Preusse, C., P. Eede, L. Heinzerling, K. Freitag, R. Koll, W. Froehlich, U. Schneider, et al. "AUTOIMMUNE & INFLAMMATORY NMD." Neuromuscular Disorders 31 (October 2021): S52. http://dx.doi.org/10.1016/j.nmd.2021.07.034.
Full text
49
Peterson, J., R. Zahedi, M. Alamr, V. Leclair, J. DiBattista, K. Nagaraju, and M. Hudson. "AUTOIMMUNE & INFLAMMATORY NMD." Neuromuscular Disorders 31 (October 2021): S50. http://dx.doi.org/10.1016/j.nmd.2021.07.027.
Full text
50
Hou, C., B. Periou, M. Gervais-Taurel, Y. Baba-Amer, F. Relaix, M. Bencze, and J. Authier. "AUTOIMMUNE & INFLAMMATORY NMD." Neuromuscular Disorders 31 (October 2021): S52. http://dx.doi.org/10.1016/j.nmd.2021.07.033.
Full text