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Biomedicines
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Nonsense-Mediated mRNA Decay: From Molecular Mechanism to Therapeutic Perspectives
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Nonsense-Mediated mRNA Decay: From Molecular Mechanism to Therapeutic Perspectives

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular Genetics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 15093

Special Issue Editor

Dr. Fabrice Lejeune

E-Mail Website
Guest Editor
CANTHER—Cancer Heterogeneity, Plasticity and Resistance to Therapies, CHU Lille, Institut Pasteur de Lille, INSERM, UMR9020-U1277, Université de Lille, 59000 Lille, France
Interests: mRNA; nonsense mutations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Quality-control mechanisms ensure the correct expression of the information contained in a gene. The most-studied quality-control mechanism is certainly that responsible for eliminating mRNAs carrying a premature stop codon, called nonsense-mediated mRNA decay (NMD). NMD was first described in yeast in 1979 by Régine Losson and François Lacroute, and it has been only 40 years since NMD was also observed in human cells by Lynne Maquat and colleagues. Since then, the molecular mechanism has been studied in detail, from the identification of the main factors involved in this mechanism to its complex connections with other cellular metabolic pathways. The interest in NMD also comes from the fact that its role as a cell cleaner of mRNAs carrying premature stop codons links it to the origin of approximately 10% of cases of genetic diseases. Some groups therefore seek to inhibit it, while others rather try to activate it, by means of various molecules, in order to propose new therapeutic approaches for the treatment of genetic diseases but also to study the mechanism of NMD in a particular configuration. Much remains to be learned about this mechanism for understanding the chains of reactions and interactions that lead to letting an mRNA continue its translation or, on the contrary, very quickly degrading an mRNA carrying a premature stop codon. A molecular understanding of this mechanism is necessary if we want to be able to control it and thus manage the fate of certain mRNAs, whether pathological or not. This Special Issue aims to provide up-to-date molecular insight into the nonsense-mediated mRNA decay mechanism, its regulation and its involvement in various pathologies.

Dr. Fabrice Lejeune
Guest Editor

Manuscript Submission Information

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Keywords

  • Premature termination codon
  • Nonsense-mediated mRNA decay
  • mRNA decay
  • UPF proteins
  • SMG proteins
  • Exon junction complex
  • P-bodies
  • Pioneer round of translation
  • Gene expression and regulation
  • Human genetic diseases

Related Special Issue

Published Papers (3 papers)

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Research

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18 pages, 3968 KiB  
Article
The NMD Pathway Regulates GABARAPL1 mRNA during the EMT
by Timothée Baudu, Chloé Parratte, Valérie Perez, Marie Ancion, Stefania Millevoi, Eric Hervouet, Anne Peigney, Paul Peixoto, Alexis Overs, Michael Herfs, Annick Fraichard, Michaël Guittaut and Aurélie Baguet
Biomedicines 2021, 9(10), 1302; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101302 - 23 Sep 2021
Cited by 1 | Viewed by 2509
Abstract
EMT is a reversible cellular process that is linked to gene expression reprogramming, which allows for epithelial cells to undergo a phenotypic switch to acquire mesenchymal properties. EMT is associated with cancer progression and cancer therapeutic resistance and it is known that, during [...] Read more.
EMT is a reversible cellular process that is linked to gene expression reprogramming, which allows for epithelial cells to undergo a phenotypic switch to acquire mesenchymal properties. EMT is associated with cancer progression and cancer therapeutic resistance and it is known that, during the EMT, many stress response pathways, such as autophagy and NMD, are dysregulated. Therefore, our goal was to study the regulation of ATG8 family members (GABARAP, GABARAPL1, LC3B) by the NMD and to identify molecular links between these two cellular processes that are involved in tumor development and metastasis formation. IHC experiments, which were conducted in a cohort of patients presenting lung adenocarcinomas, showed high GABARAPL1 and low UPF1 levels in EMT+ tumors. We observed increased levels of GABARAPL1 correlated with decreased levels of NMD factors in A549 cells in vitro. We then confirmed that GABARAPL1 mRNA was indeed targeted by the NMD in a 3′UTR-dependent manner and we identified four overlapping binding sites for UPF1 and eIF4A3 that are potentially involved in the recognition of this transcript by the NMD pathway. Our study suggests that 3′UTR-dependent NMD might be an important mechanism that is involved in the induction of autophagy and could represent a promising target in the development of new anti-cancer therapies. Full article
(This article belongs to the Special Issue Nonsense-Mediated mRNA Decay: From Molecular Mechanism to Therapeutic Perspectives)
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Review

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11 pages, 616 KiB  
Review
Nonsense-Mediated mRNA Decay, a Finely Regulated Mechanism
by Fabrice Lejeune
Biomedicines 2022, 10(1), 141; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010141 - 10 Jan 2022
Cited by 25 | Viewed by 7188
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Nonsense-Mediated mRNA Decay: From Molecular Mechanism to Therapeutic Perspectives)
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12 pages, 758 KiB  
Review
UPF1: From mRNA Surveillance to Protein Quality Control
by Hyun Jung Hwang, Yeonkyoung Park and Yoon Ki Kim
Biomedicines 2021, 9(8), 995; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080995 - 11 Aug 2021
Cited by 14 | Viewed by 4422
Abstract
Selective recognition and removal of faulty transcripts and misfolded polypeptides are crucial for cell viability. In eukaryotic cells, nonsense-mediated mRNA decay (NMD) constitutes an mRNA surveillance pathway for sensing and degrading aberrant transcripts harboring premature termination codons (PTCs). NMD functions also as a [...] Read more.
Selective recognition and removal of faulty transcripts and misfolded polypeptides are crucial for cell viability. In eukaryotic cells, nonsense-mediated mRNA decay (NMD) constitutes an mRNA surveillance pathway for sensing and degrading aberrant transcripts harboring premature termination codons (PTCs). NMD functions also as a post-transcriptional gene regulatory mechanism by downregulating naturally occurring mRNAs. As NMD is activated only after a ribosome reaches a PTC, PTC-containing mRNAs inevitably produce truncated and potentially misfolded polypeptides as byproducts. To cope with the emergence of misfolded polypeptides, eukaryotic cells have evolved sophisticated mechanisms such as chaperone-mediated protein refolding, rapid degradation of misfolded polypeptides through the ubiquitin–proteasome system, and sequestration of misfolded polypeptides to the aggresome for autophagy-mediated degradation. In this review, we discuss how UPF1, a key NMD factor, contributes to the selective removal of faulty transcripts via NMD at the molecular level. We then highlight recent advances on UPF1-mediated communication between mRNA surveillance and protein quality control. Full article
(This article belongs to the Special Issue Nonsense-Mediated mRNA Decay: From Molecular Mechanism to Therapeutic Perspectives)
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