scholarly journals Regulation of nonsense-mediated mRNA decay in neural development and disease

2021 ◽  
Author(s):  
Paul Jongseo Lee ◽  
Suzhou Yang ◽  
Yu Sun ◽  
Junjie U Guo
Keyword(s):  
Neural Development ◽  
Mrna Decay ◽  
Developmental Regulation ◽  
Critical Role ◽  
Premature Termination Codon ◽  
Regulation Mechanism ◽  
Genes Encoding ◽  
Nonsense Mediated Mrna Decay ◽  
Quality Control Mechanism

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 (PTC), but also as a post-transcriptional 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.

scholarly journals Nonsense-Mediated mRNA Decay Mutation in Aspergillus nidulans

2006 ◽  
Vol 5 (11) ◽  
pp. 1838-1846 ◽  
Author(s):  
Igor Y. Morozov ◽  
Susana Negrete-Urtasun ◽  
Joan Tilburn ◽  
Christine A. Jansen ◽  
Mark X. Caddick ◽  
...  
Keyword(s):  
Aspergillus Nidulans ◽  
Mrna Decay ◽  
Premature Termination ◽  
Regulation Of Gene Expression ◽  
Premature Termination Codon ◽  
Termination Codon ◽  
Urate Oxidase ◽  
Genes Encoding ◽  
Nonsense Mediated Mrna Decay ◽  
Nonsense Codons

ABSTRACT An Aspergillus nidulans mutation, designated nmdA1, has been selected as a partial suppressor of a frameshift mutation and shown to truncate the homologue of the Saccharomyces cerevisiae nonsense-mediated mRNA decay (NMD) surveillance component Nmd2p/Upf2p. nmdA1 elevates steady-state levels of premature termination codon-containing transcripts, as demonstrated using mutations in genes encoding xanthine dehydrogenase (hxA), urate oxidase (uaZ), the transcription factor mediating regulation of gene expression by ambient pH (pacC), and a protease involved in pH signal transduction (palB). nmdA1 can also stabilize pre-mRNA (unspliced) and wild-type transcripts of certain genes. Certain premature termination codon-containing transcripts which escape NMD are relatively stable, a feature more in common with certain nonsense codon-containing mammalian transcripts than with those in S. cerevisiae. As in S. cerevisiae, 5′ nonsense codons are more effective at triggering NMD than 3′ nonsense codons. Unlike the mammalian situation but in common with S. cerevisiae and other lower eukaryotes, A. nidulans is apparently impervious to the position of premature termination codons with respect to the 3′ exon-exon junction.

Aberrant termination triggers nonsense-mediated mRNA decay

2006 ◽  
Vol 34 (1) ◽  
pp. 39-42 ◽  
Author(s):  
N. Amrani ◽  
S. Dong ◽  
F. He ◽  
R. Ganesan ◽  
S. Ghosh ◽  
...  
Keyword(s):  
Quality Control ◽  
Untranslated Region ◽  
Mrna Decay ◽  
Premature Termination ◽  
Control Mechanism ◽  
Premature Termination Codon ◽  
Release Factor ◽  
Mrna Decapping ◽  
Nonsense Mediated Mrna Decay ◽  
Quality Control Mechanism

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.

scholarly journals Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies

2007 ◽  
Vol 178 (7) ◽  
pp. 1145-1160 ◽  
Author(s):  
Sébastien Durand ◽  
Nicolas Cougot ◽  
Florence Mahuteau-Betzer ◽  
Chi-Hung Nguyen ◽  
David S. Grierson ◽  
...  
Keyword(s):  
Quality Control ◽  
Mrna Decay ◽  
Control Mechanism ◽  
Premature Termination Codon ◽  
Processing Bodies ◽  
P Bodies ◽  
Molecule Inhibitor ◽  
Nonsense Mediated Mrna Decay ◽  
Quality Control Mechanism ◽  
Insight Into

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.

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 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 The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 49 ◽  
Author(s):  
Francesca Degrassi ◽  
Michela Damizia ◽  
Patrizia Lavia
Keyword(s):  
Chromosome Instability ◽  
Critical Role ◽  
Somatic Cells ◽  
Neuronal Cell ◽  
Mitotic Division ◽  
Special Focus ◽  
Mitotic Apparatus ◽  
Genes Encoding ◽  
Congenital Microcephaly

Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental diseases. Here, we briefly summarize existing knowledge on how microcephaly-related mitotic genes operate in the control of chromosome segregation during mitosis in somatic cells, with a special focus on the role of kinetochore factors. Then, we review evidence implicating mitotic apparatus- and kinetochore-resident factors in the origin of congenital microcephaly. We discuss data emerging from these works, which suggest a critical role of correct mitotic division in controlling neuronal cell proliferation and shaping the architecture of the central nervous system.

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.

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