scholarly journals Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 765 ◽  
Author(s):  
Kamila Pawlicka ◽  
Umesh Kalathiya ◽  
Javier Alfaro
Keyword(s):  
Messenger Rna ◽  
Mrna Decay ◽  
Tumour Progression ◽  
Transcript Abundance ◽  
Tumour Suppressor Genes ◽  
Nonsense Mediated Mrna Decay ◽  
The Many ◽  
Cycle Regulation ◽  
Fine Tune

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.

scholarly journals A Haploid Genetic Screening Method for Proteins Influencing Mammalian Nonsense-Mediated mRNA Decay Activity

2018 ◽  
Author(s):  
Maximilian W. Popp ◽  
Lynne E. Maquat
Keyword(s):  
Genetic Screening ◽  
Mammalian Cells ◽  
Mrna Decay ◽  
Fluorescent Proteins ◽  
Screening Method ◽  
Transcript Abundance ◽  
Exon Junction Complex ◽  
Exon Junction ◽  
Nonsense Mediated Mrna Decay

AbstractDespite a long appreciation for the role of nonsense-mediated mRNA decay (NMD) in the destruction of faulty, disease-causing mRNAs, as well as its role in the maintenance of normal, endogenous transcript abundance, systematic unbiased methods for uncovering modifiers of NMD activity in mammalian cells remain scant. Here we present and validate a haploid genetic screening method for identifying proteins and processes that stimulate NMD activity involving a 3′-untranslated region exon-junction complex. This reporterbased screening method can be adapted for interrogating other pathways whose output can be measured by the intracellular production of fluorescent proteins.

scholarly journals Identification and characterization of a sequence motif involved in nonsense-mediated mRNA decay.

1995 ◽  
Vol 15 (4) ◽  
pp. 2231-2244 ◽  
Author(s):  
S Zhang ◽  
M J Ruiz-Echevarria ◽  
Y Quan ◽  
S W Peltz
Keyword(s):  
Mrna Decay ◽  
Sequence Motif ◽  
Nonsense Mutations ◽  
Stem Loop ◽  
Cis Acting ◽  
Stem Loop Structure ◽  
Nonsense Codon ◽  
Nonsense Mediated Mrna Decay

In both prokaryotes and eukaryotes, nonsense mutations in a gene can enhance the decay rate or reduce the abundance of the mRNA transcribed from that gene, and we call this process nonsense-mediated mRNA decay. We have been investigating the cis-acting sequences involved in this decay pathway. Previous experiments have demonstrated that, in addition to a nonsense codon, specific sequences 3' of a nonsense mutation, which have been defined as downstream elements, are required for mRNA destabilization. The results presented here identify a sequence motif (TGYYGATGYYYYY, where Y stands for either T or C) that can predict regions in genes that, when positioned 3' of a nonsense codon, promote rapid decay of its mRNA. Sequences harboring two copies of the motif from five regions in the PGK1, ADE3, and HIS4 genes were able to function as downstream elements. In addition, four copies of this motif can function as an independent downstream element. The sequences flanking the motif played a more significant role in modulating its activity when fewer copies of the sequence motif were present. Our results indicate the sequences 5' of the motif can modulate its activity by maintaining a certain distance between the sequence motif and the termination codon. We also suggest that the sequences 3' of the motif modulate the activity of the downstream element by forming RNA secondary structures. Consistent with this view, a stem-loop structure positioned 3' of the sequence motif can enhance the activity of the downstream element. This sequence motif is one of the few elements that have been identified that can predict regions in genes that can be involved in mRNA turnover. The role of these sequences in mRNA decay is discussed.

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 Characterisation of the Semliki Forest Virus-host cell interactome reveals the viral capsid protein as an inhibitor of nonsense-mediated mRNA decay

2020 ◽  
Author(s):  
Lara Contu ◽  
Giuseppe Balistreri ◽  
Michal Domanski ◽  
Anne-Christine Uldry ◽  
Oliver Mühlemann
Keyword(s):  
Host Cell ◽  
Capsid Protein ◽  
Mrna Decay ◽  
Semliki Forest Virus ◽  
Protein Protein Interaction ◽  
Host Cell Proteins ◽  
Complex Interactions ◽  
Nonsense Mediated Mrna Decay ◽  
Interaction Map ◽  
The Many

AbstractThe positive-sense, single-stranded RNA alphaviruses pose a potential epidemic threat. Understanding the complex interactions between the viral and the host cell proteins is crucial for elucidating the mechanisms underlying successful virus replication strategies and for developing specific antiviral interventions. Here we present the first comprehensive protein-protein interaction map between the proteins of Semliki Forest Virus (SFV), a mosquito-borne member of the alphaviruses, and host cell proteins. Among the many identified cellular interactors of SFV proteins, the enrichment of factors involved in translation and nonsense-mediated mRNA decay (NMD) was striking, reflecting the virus’ hijacking of the translation machinery and indicating viral countermeasures for escaping NMD by inhibiting NMD at later time points during the infectious cycle. In addition to observing a general inhibition of NMD about 4 hours post infection, we also demonstrate that transient expression of the SFV capsid protein is sufficient to inhibit NMD in cells, suggesting that the massive production of capsid protein during the SFV reproduction cycle is responsible for NMD inhibition.

Nonsense-Mediated mRNA Decay Is Essential for the Hematopietic Compartement.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 506-506
Author(s):  
Joachim Weischenfeldt ◽  
Inge Damgaard ◽  
David Bryder ◽  
Claus Nerlov ◽  
Bo Porse
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
T Cells ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Mrna Decay ◽  
Double Positive ◽  
Mrna Pool ◽  
Nonsense Mediated Mrna Decay

Abstract Nonsense-mediated mRNA decay (NMD) is a conserved cellular surveillance system that degrades mRNAs with premature termination codons (PTCs). PTC-containing transcripts can arise from faulty events such as erroneous mRNA processing events as well as mutations, and their translation may lead to the synthesis of deleterious proteins. In addition to serving as a genomic protection system, experiments in tissue culture cells have demonstrated that NMD regulates 5% of the normal mRNA pool suggesting that the NMD pathway may have a broader role in gene regulation. Finally, NMD has also been proposed to be important during lymphocyte development as a tool of riding the cells of transcripts resulting from unproductive re-arrangements events of T cell receptor and immunoglobulin genes. Although NMD has been studied extensively at the biochemical level, the actual role and importance of NMD in the mammalian organism has not been investigated. We therefore generated a conditional Upf2 knock-out mouse line (UPF2 being an essential NMD factor) which we crossed to different hematopoietic relevant Cre expressing lines. Full ablation of UPF2 (using the inducible Mx1-Cre deleter) led to complete loss of all nucleated cells in the bone marrow and death of the animals within 10 days. A similar phenotype was observed when Upf2fl/fl; Mx1Cre BM cells were transplanted into lethally irradiated WT recipients and induced with poly-IC, demonstrating the cell autonomous nature of the phenotype. Deletion of UPF2 in the myeloid lineage using the LysM-Cre deleter resulted in efficient ablation of UPF2 and the absence of NMD in reporter transfected bone marrow derived macrophages (BMDMs). However, the steady state levels of myeloid cells appeared unaltered. Finally, deletion of UPF2 in T cells using a Lck-Cre deleter led to a marked reduction of both CD4/CD8 double-positive and single-positive T cells and accumulation of PTC containing transcripts. Gene expression profiling experiments of BMDM and thymocytes from WT and UPF2-ablated animals identified a common core set of 27 up-regulated genes consistent with the role of NMD as a mRNA degrading system. The gene expression profiling data suggest that ablation of NMD leads to accumulation of unfolded proteins. In summary, these studies demonstrate the vital and cell-autonomous role of NMD in the hematopoietic system.

scholarly journals The role of autophagy in tumour development and cancer therapy

2009 ◽  
Vol 11 ◽  
Author(s):  
Mathias T. Rosenfeldt ◽  
Kevin M. Ryan
Keyword(s):  
Membrane Trafficking ◽  
Energy Production ◽  
Malignant Disease ◽  
Human Cancer ◽  
Tumour Progression ◽  
Current Evidence ◽  
Tumour Suppressor Genes ◽  
Normal Tissues ◽  
Promote Cell Survival

Autophagy is a catabolic membrane-trafficking process that leads to sequestration and degradation of intracellular material within lysosomes. It is executed at basal levels in every cell and promotes cellular homeostasis by regulating organelle and protein turnover. In response to various forms of cellular stress, however, the levels and cargoes of autophagy can be modulated. In nutrient-deprived states, for example, autophagy can be activated to degrade cargoes for cell-autonomous energy production to promote cell survival. In other contexts, in contrast, autophagy has been shown to contribute to cell death. Given these dual effects in regulating cell viability, it is no surprise that autophagy has implications in both the genesis and treatment of malignant disease. In this review, we provide a comprehensive appraisal of the way in which oncogenes and tumour suppressor genes regulate autophagy. In addition, we address the current evidence from human cancer and animal models that has aided our understanding of the role of autophagy in tumour progression. Finally, the potential for targeting autophagy therapeutically is discussed in light of the functions of autophagy at different stages of tumour progression and in normal tissues.

Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay

2008 ◽  
Vol 29 (2) ◽  
pp. 277-283 ◽  
Author(s):  
Gisela Nogales-Gadea ◽  
Juan Carlos Rubio ◽  
Israel Fernandez-Cadenas ◽  
Ines Garcia-Consuegra ◽  
Alejandro Lucia ◽  
...  
Keyword(s):  
Muscle Glycogen ◽  
Glycogen Phosphorylase ◽  
Mrna Decay ◽  
Mcardle Disease ◽  
Nonsense Mediated Mrna Decay

scholarly journals CLK-2/TEL2 is a conserved component of the nonsense-mediated mRNA decay pathway

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244505
Author(s):  
Yanwu Guo ◽  
Cristina Tocchini ◽  
Rafal Ciosk
Keyword(s):  
Mrna Decay ◽  
Forward Genetics ◽  
Morphological Effect ◽  
Dna Damage Signaling ◽  
Mrna Surveillance ◽  
Genetic Landscape ◽  
Nonsense Mediated Mrna Decay ◽  
Novel Strategy ◽  
Conserved Gene

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.

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