Article
Biochemistry & Molecular Biology
Sarah E. Fritz, Soumya Ranganathan, Clara D. Wang, J. Robert Hogg
Summary: This study reveals that an alternative isoform of the core NMD factor UPF1, UPF1(LL), can remodel the specificity of NMD in response to cellular stress. UPF1(LL) is able to bypass specific protective RNA binding proteins, bind and down-regulate transcripts with long 3'UTRs, and induce NMD in response to cellular stress conditions.
Article
Biochemistry & Molecular Biology
Sebastian Grosse, Yen-Yun Lu, Ivo Coban, Bettina Neumann, Heike Krebber
Summary: This study revealed that Gbp2 and Hrb1 are involved in nonsense mediated decay of premature termination codon-containing mRNAs by forming a complex with Upf proteins. They aid in transmitting PTC recognition signals and promoting translation repression and RNA degradation, thus controlling mRNA quality beyond the nuclear border. Identification of SR proteins as global surveillance factors in yeast sheds light on their potential role in understanding the complex human system with diseases related to defects in SR proteins or NMD.
Article
Biochemistry & Molecular Biology
Fabrice Lejeune
Summary: Nonsense-mediated mRNA decay (NMD) is a mechanism for rapidly eliminating mRNAs with premature termination codons and also regulates multiple genes. Researchers have discovered that NMD must be regulated to express genes that are normally repressed by NMD under specific physiological conditions, so a comprehensive understanding of NMD regulation is important for therapeutic purposes.
Article
Biochemistry & Molecular Biology
Zhongxia Yi, Rene M. Arvola, Sean Myers, Corinne N. Dilsavor, Rabab Abu Alhasan, Bayley N. Carter, Robert D. Patton, Ralf Bundschuh, Guramrit Singh
Summary: This study reveals that nonsense-mediated mRNA decay (NMD) in human cell lines can be dependent on UPF3B or independent of it. UPF3A only weakly activates NMD in wild-type cells, but strongly activates NMD in cells lacking UPF3B.
Review
Cell Biology
Paul Jongseo Lee, Suzhou Yang, Yu Sun, Junjie U. Guo
Summary: Eukaryotes have evolved various mRNA surveillance mechanisms, with NMD functioning as a quality control mechanism and posttranscriptional gene regulation.
JOURNAL OF MOLECULAR CELL BIOLOGY
(2021)
Article
Clinical Neurology
Gabrielle Zuniga, Simon Levy, Paulino Ramirez, Jasmine De Mange, Elias Gonzalez, Maria Gamez, Bess Frost
Summary: This study investigates the mechanisms behind altered RNA processing in tauopathies, specifically focusing on the reduction of nonsense-mediated mRNA decay (NMD) activity. The researchers find that deficits in NMD contribute to neurodegeneration in tauopathy through aberrant RNA export and accumulation. They identify a pharmacological activator of NMD that suppresses neurodegeneration in a tau transgenic Drosophila model, suggesting potential therapeutic value for tauopathy patients.
ALZHEIMERS & DEMENTIA
(2023)
Review
Genetics & Heredity
Preeti Nagar, Md Rafikul Islam, Mohammad Alinoor Rahman
Summary: NMD is a mechanism that ensures gene expression accuracy and regulation by degrading erroneous transcripts and modulating the abundance of endogenous mRNAs. It plays diverse biological functions during development, adaptation, and stress response. In tumorigenesis, NMD can be exploited by tumor cells to degrade specific mRNAs or suppressed to promote the expression of oncoproteins.
Review
Virology
Md Robel Ahmed, Zhiyou Du
Summary: The interaction between viruses and hosts is dynamic and evolutionary. Eukaryotic hosts have multiple defense mechanisms against viral infection, including the nonsense-mediated mRNA decay (NMD) system. NMD ensures the accuracy of mRNA translation by degrading abnormal mRNAs. Many RNA viruses have internal stop codons (iTC), which activate NMD and lead to degradation of viral genomes. Some viruses are sensitive to NMD-mediated antiviral defense, while others have evolved mechanisms to overcome or escape NMD. This review summarizes the current understanding of NMD-mediated viral RNA degradation and the ways in which viruses compromise NMD for better infection.
Article
Biochemistry & Molecular Biology
Damaris Wallmeroth, Jan-Wilm Lackmann, Sabrina Kueckelmann, Janine Altmueller, Christoph Dieterich, Volker Boehm, Niels H. Gehring
Summary: The paralogous proteins UPF3A and UPF3B in humans play important roles in recognizing mRNAs targeted by nonsense-mediated mRNA decay (NMD). UPF3B supports NMD by bridging an exon junction complex (EJC) to the NMD factor UPF2. The role of UPF3A has been described as either a weak NMD activator or an NMD inhibitor. However, knockout or overexpression of UPF3A or knockout of UPF3B did not significantly affect global NMD activity. Co-depletion of UPF3A and UPF3B resulted in NMD inhibition, indicating functional redundancy between these two NMD factors.
Article
Biochemistry & Molecular Biology
Julie Carrard, Fiona Ratajczak, Josephine Elsens, Catherine Leroy, Rebekah Kong, Lucie Geoffroy, Arnaud Comte, Guy Fournet, Benoit Joseph, Xiubin Li, Sylvie Moebs-Sanchez, Fabrice Lejeune
Summary: The study has built a new screening system and identified two new molecules that can effectively inhibit nonsense-mediated mRNA decay (NMD). These molecules show no cellular toxicity at tested concentrations and have been validated in a lung cancer model with a nonsense mutation.
Article
Multidisciplinary Sciences
Volker Boehm, Sabrina Kueckelmann, Jennifer Gerbracht, Sebastian Kallabis, Thiago Britto-Borges, Janine Altmueller, Marcus Krueger, Christoph Dieterich, Niels H. Gehring
Summary: The degradation of nonsense-mediated mRNA decay (NMD) substrates involves two independent pathways, SMG6-mediated endonucleolytic cleavage and/or SMG5-SMG7-induced accelerated deadenylation. SMG5-SMG7 maintain NMD activity by enabling SMG6 activation. The loss of SMG5-SMG7-dependent pathway can also inactivate the SMG6-dependent branch, indicating a functional connection between the final NMD steps.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Lingling Sun, Justine Mailliot, Christiane Schaffitzel
Summary: Nonsense-mediated mRNA decay (NMD) is a cellular surveillance mechanism that degrades mRNAs with a premature stop codon and downregulates the expression of endogenous transcripts. The core NMD factors are conserved from yeast to human, but mammals have diversified NMD pathways with additional factors. This review summarizes the molecular mechanisms and cellular roles of NMD and discusses its implications in neurodevelopmental diseases, cancer, and strategies used by RNA viruses to evade recognition by the NMD machinery.
Review
Neurosciences
Marija Petrie Howe, Rickie Patani
Summary: The processes of mRNA export and translation play important roles in gene expression regulation in eukaryotic cells, particularly in highly polarised cells like neurons. Nonsense-mediated mRNA decay (NMD) is a translation-dependent quality control process that regulates gene expression in the nervous system and is involved in neurodevelopment, learning, and memory formation. Dysregulation of NMD has been linked to various neurodevelopmental and neurodegenerative disorders. This article discusses the role of NMD and mRNA translation in neuronal functions, with a focus on their involvement in the molecular pathogenesis of neurodegeneration. Additionally, it explores the therapeutic potential and challenges of targeting these processes in neurological diseases that currently lack effective treatments.
TRENDS IN NEUROSCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Monica Mesa-Perez, Phineas T. Hamilton, Alex Miranda, Nicholas Brodie, Connor O'Sullivan, Jennifer Christie, Bridget C. Ryan, Robert L. Chow, David Goodlett, Christopher J. Nelson, Perry L. Howard
Summary: The lifecycle of RNA polymerase II (RNAPII) transcripts is influenced by the formation of mutually exclusive ribonucleoprotein complexes (RNPs) that guide transcript generation and degradation. A recent study reveals that the scaffold protein ARS2, bound to the cap binding complex (CBC), regulates RNA metabolism in the nucleus. Interestingly, alternative splicing of ARS2 generates cytoplasmic isoforms that exhibit different functions from their nuclear counterparts, suggesting their importance in cellular homeostasis and stress response.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Cell Biology
Alison J. Inglis, Alina Guna, Angel Galvez-Merchan, Akshaye Pal, Theodore K. Esantsi, Heather R. Keys, Evgeni M. Frenkel, Robert Oania, Jonathan S. Weissman, Rebecca M. Voorhees
Summary: Translation of mRNAs containing premature termination codons (PTCs) results in truncated protein products with deleterious effects. Nonsense-mediated decay (NMD) is responsible for detecting and degrading these proteins, and it relies on the ubiquitin proteasome pathway. Screening experiments identified factors involved in NMD-associated protein quality control and revealed a shared recognition event for both mRNA and protein branches of NMD.
JOURNAL OF CELL SCIENCE
(2023)
Correction
Biochemistry & Molecular Biology
Katharina Schubert, Evangelos D. Karousis, Ahmad Jomaa, Alain Scaiola, Blanca Echeverria, Lukas-Adrian Gurzeler, Marc Leibundgut, Volker Thiel, Oliver Muhlemann, Nenad Ban
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Katharina Schubert, Evangelos D. Karousis, Ahmad Jomaa, Alain Scaiola, Blanca Echeverria, Lukas-Adrian Gurzeler, Marc Leibundgut, Volker Thiel, Oliver Muehlemann, Nenad Ban
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Giuditta Annibaldis, Michal Domanski, Rene Dreos, Lara Contu, Sarah Carl, Nina Klaey, Oliver Muehlemann
NUCLEIC ACIDS RESEARCH
(2020)
Article
Multidisciplinary Sciences
Evangelos D. Karousis, Lukas-Adrian Gurzeler, Giuditta Annibaldis, Rene Dreos, Oliver Muehlemann
NATURE COMMUNICATIONS
(2020)
Article
Biochemistry & Molecular Biology
Stefan Reber, Daniel Jutzi, Helen Lindsay, Anny Devoy, Jonas Mechtersheimer, Brunno Rocha Levone, Michal Domanski, Eva Bentmann, Dorothee Dormann, Oliver Muehlemann, Silvia M. L. Barabino, Marc-David Ruepp
Summary: Liquid-liquid phase separation (LLPS) of proteins and RNAs is critical in the formation of membrane-less organelles, leading to biomolecular condensates with diverse biological functions and disease implications. The Fused in Sarcoma (FUS) protein undergoes LLPS and its mutations are linked to Amyotrophic Lateral Sclerosis (ALS-FUS). The study shows that LLPS shapes the interactome of FUS in cells, affecting its function and disease outcomes.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Yeonkyoung Park, Joori Park, Hyun Jung Hwang, Leehyeon Kim, Kwon Jeong, Hyun Kyu Song, Simone C. Rufener, Oliver Muehlemann, Yoon Ki Kim
Summary: It has been demonstrated that CTIF is tethered to the perinuclear region by DDX19B in a translationally incompetent manner, and then handed over to CBP80, which is associated with the 5'-cap of newly exported mRNA, initiating CBC-dependent translation in the perinuclear region. Disrupting the interaction between CTIF and DDX19B leads to uncontrolled translation in the cytosol, ultimately affecting nonsense-mediated mRNA decay. This highlights the importance of tight control of local translation in the perinuclear region.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Microbiology
Lara Contu, Giuseppe Balistreri, Michal Domanski, Anne-Christine Uldry, Oliver Muhlemann
Summary: Understanding the interactions between Semliki Forest Virus proteins and host cell proteins is crucial for understanding the mechanisms by which the virus replicates successfully and develops specific antiviral interventions. The study shows that the virus hijacks the translation machinery and inhibits NMD to escape the host cell's defense mechanisms, with the capsid protein playing a key role in inhibiting NMD during the infectious cycle.
Article
Biochemistry & Molecular Biology
Lukas-Adrian Gurzeler, Jana Ziegelmueller, Oliver Muehlemann, Evangelos D. Karousis
Summary: This study introduces a robust and fast method for detergent-free cell lysis under controlled mechanical forces, which can produce translation-competent lysates from human cells and enhance protein output by reducing the phosphorylation state of eIF2 alpha.
Review
Biochemistry & Molecular Biology
Evangelos D. Karousis, Oliver Muehlemann
Summary: The article reviews the important role of NMD in mRNA degradation, discusses its impact on various diseases, and proposes strategies to modulate NMD as potential therapeutic approaches.
TRENDS IN BIOCHEMICAL SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Katharina Schubert, Evangelos D. Karousis, Ivo Ban, Christopher P. Lapointe, Marc Leibundgut, Emilie Baumlin, Eric Kummerant, Alain Scaiola, Tanja Schonhut, Jana Ziegelmuller, Joseph D. Puglisi, Oliver Muhlemann, Nenad Ban
Summary: The study investigated Nsp1 from SARS-CoV-2, MERS-CoV, and Bat-Hp-CoV coronaviruses, revealing a conserved role for the C-terminal domain. Additionally, the N-terminal domain of Bat-Hp-CoV Nsp1 was found to bind to the decoding center of the 40S subunit, preventing mRNA and eIF1A accommodation. Structure-based experiments demonstrated the importance of decoding center interactions in all three coronaviruses and showed that the same regions of Nsp1 are necessary for the selective translation of viral RNAs.
Article
Cell Biology
Lukas-Adrian Gurzeler, Marion Link, Yvonne Ibig, Isabel Schmidt, Olaf Galuba, Julian Schoenbett, Christelle Gasser-Didierlaurant, Christian N. Parker, Xiaohong Mao, Francis Bitsch, Markus Schirle, Philipp Couttet, Frederic Sigoillot, Jana Ziegelmueller, Anne-Christine Uldry, Wojciech Teodorowicz, Niko Schmiedeberg, Oliver Muhlemann, Jurgen Reinhardt
Summary: This study discovered two potent readthrough promoters that can restore full-length functional proteins in disease models. Unlike other readthrough promoters, these compounds stimulate premature termination codon suppression by promoting the degradation of the translation termination factor eRF1.
Article
Biotechnology & Applied Microbiology
Evangelos D. Karousis, Foivos Gypas, Mihaela Zavolan, Oliver Muehlemann
Summary: The study utilized long-read sequencing and short-read sequencing to identify and analyze endogenous targets of nonsense-mediated mRNA decay (NMD) in human cells. It discovered many novel NMD-sensitive mRNA isoforms, most of which derive from alternative exon usage, and revealed the role of NMD in regulating gene expression through splicing signals analysis.
