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
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
Multidisciplinary Sciences
Georgia Katsioudi, Rene Dreos, Enes S. Arpa, Sevasti Gaspari, Angelica Liechti, Miho Sato, Christian H. Gabriel, Achim Kramer, Steven A. Brown, David Gatfield
Summary: The study demonstrates the importance of nonsense-mediated mRNA decay (NMD) in physiological control, particularly in regulating the circadian clock and gene expression.
Article
Biotechnology & Applied Microbiology
Bo Sun, Liang Chen
Summary: Through genetical genomics, we elucidate the regulatory mechanism of NMD on individual genes across human tissues. We identify genetic variants that influence NMD regulation, which are often missed in traditional eQTL mapping. NMD regulation plays important roles in the brain and has specific genomic positions for NMD-QTLs.
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
Multidisciplinary Sciences
Young Jin Kim, Tomoki Nomakuchi, Foteini Papaleonidopoulou, Lucia Yang, Qian Zhang, Adrian R. Krainer
Summary: An antisense oligonucleotide cocktail has been developed to restore CFTR protein function by gene-specific stabilization of CFTR mRNA and increase the expression of CFTR-W1282X mRNA, providing a potential therapy for cystic fibrosis caused by the W1282X mutation. The treatment has been shown to enhance CFTR-mediated chloride current in human bronchial epithelial cells.
NATURE COMMUNICATIONS
(2022)
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.
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
Genetics & Heredity
Zhongxia Yi, Manu Sanjeev, Guramrit Singh
Summary: Nonsense-mediated mRNA decay (NMD) is a conserved translation-coupled quality control mechanism in all eukaryotes, especially crucial in vertebrates. In vertebrates, NMD is a complex, branched pathway that regulates specific mRNA subsets to fulfill distinct physiological functions.
TRENDS IN GENETICS
(2021)
Review
Biochemistry & Molecular Biology
Justine Mailliot, Mirella Vivoli-Vega, Christiane Schaffitzel
Summary: Nonsense-mediated messenger RNA decay (NMD) is an important mRNA degradation pathway in eukaryotic cells, controlling mRNA quality and abundance, as well as degrading viral RNA. NMD recognizes mRNAs with premature termination codons (PTCs) and targets them for degradation through a branched network of interconnected pathways. The structural understanding and functional interplay of mammalian NMD factors, such as UPF1, UPF3B, and UPF3A, play crucial roles in NMD pathway choice and regulation. The context-dependent nature of mammalian NMD, determined by developmental stage, tissue, and cell types, further highlights the complexity of gene regulation in this pathway.
BIOCHEMICAL JOURNAL
(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)
Article
Biochemical Research Methods
Joel I. Perez-Perri, Marko Noerenberg, Wael Kamel, Caroline E. Lenz, Shabaz Mohammed, Matthias W. Hentze, Alfredo Castello
Summary: Interactions between RNA-binding proteins (RBPs) and RNAs play a critical role in cell biology, and the RNA interactome capture (RIC) method allows for comprehensive and quantitative assessment of these interactions using UV crosslinking, oligo(dT) capture, and proteomics. Recent advancements have enhanced RIC by utilizing LNA probes with stronger binding affinity and SILAC/TMT proteomic techniques, improving RBP quantification accuracy and reproducibility in response to biological cues like metabolic imbalance or virus infection.
Review
Genetics & Heredity
Fatima Gebauer, Thomas Schwarzl, Juan Valcarcel, Matthias W. Hentze
Summary: RNA-binding proteins (RBPs) are key effectors of gene expression, and their malfunction leads to various diseases. RBPs play important roles in human genetic disorders, with emerging therapeutic interventions targeting RBPs.
NATURE REVIEWS GENETICS
(2021)
Article
Cell Biology
Eva Riechert, Vivien Kmietczyk, Frank Stein, Thomas Schwarzl, Thileepan Sekaran, Lonny Juergensen, Verena Kamuf-Schenk, Eshita Varma, Christoph Hofmann, Mandy Rettel, Kira Guer, Julie Oelschlaeger, Friederike Kuehl, Judit Martin, Marta Ramirez-Pedraza, Mercedes Fernandez, Shirin Doroudgar, Raul Mendez, Hugo A. Katus, Matthias W. Hentze, Mirko Voelkers
Summary: RNA-binding proteins (RBPs) play a critical role in controlling cardiomyocyte function, and the cytoplasmic polyadenylation element-binding protein 4 (Cpeb4) is identified as a key regulator of cardiac growth and remodeling by differential binding to specific mRNAs. This study reveals a system-wide view of active RBPs in cardiomyocytes during growth response, shedding light on their role in regulating cardiomyocyte function.
Article
Multidisciplinary Sciences
Jonas P. Becker, Dominic Helm, Mandy Rettel, Frank Stein, Alejandro Hernandez-Sanchez, Katharina Urban, Johannes Gebert, Matthias Kloor, Gabriele Neu-Yilik, Magnus von Knebel Doeberitz, Matthias W. Hentze, Andreas E. Kulozik
Summary: The study reveals that pharmacological inhibition of RNA decay mechanism NMD enhances HLA-I-mediated tumor-specific T cell immune responses, indicating a potential clinical application in anti-cancer immunotherapy.
Article
Hematology
Lena Muckenthaler, Oriana Marques, Silvia Colucci, Joachim Kunz, Piotr Fabrowski, Thomas Bast, Sandro Altamura, Britta Hochsmann, Hubert Schrezenmeier, Monika Langlotz, Paulina Richter-Pechanska, Tobias Rausch, Nicole Hofmeister-Mielke, Nikolas Gunkel, Matthias W. Hentze, Andreas E. Kulozik, Martina U. Muckenthaler
Review
Biochemical Research Methods
Gianluca Sigismondo, Dimitris N. Papageorgiou, Jeroen Krijgsveld
Summary: Chromatin is composed of genomic DNA and proteins in the nucleus of eukaryotic cells, playing a crucial role in regulating cellular processes. Histones, the best known protein constituents in chromatin, undergo post-translational modifications to recruit accessory proteins for specific functions. Proteomic approaches have been instrumental in understanding the complex interplay within chromatin, enabling the identification and quantification of proteins and modifications in an unbiased manner.
Article
Biochemistry & Molecular Biology
Magdalena Buescher, Rastislav Horos, Ina Huppertz, Kevin Haubrich, Nikolay Dobrev, Florence Baudin, Janosch Hennig, Matthias W. Hentze
Summary: This study reveals the mechanism by which vault RNA1-1 inhibits the oligomerization of p62 through biochemical and functional experiments. The PB1 domain and adjacent linker region of p62 (aa 1-122) are identified as critical for specific binding with vault RNA1-1, and lysine 7 and arginine 21 are identified as key hinges for p62 riboregulation. Additionally, chemical structure probing of vault RNA1-1 identifies a central flexible loop that is required for the specific interaction with p62.
Article
Biochemistry & Molecular Biology
Ina Huppertz, Joel I. Perez-Perri, Panagiotis Mantas, Thileepan Sekaran, Thomas Schwarzl, Francesco Russo, Dunja Ferring-Appel, Zuzana Koskova, Lyudmila Dimitrova-Paternoga, Eleni Kafkia, Janosch Hennig, Pierre A. Neveu, Kiran Patil, Matthias W. Hentze
Summary: The study reveals acetylation-driven riboregulation of ENO1 as a physiological mechanism of glycolytic control and stem cell differentiation regulation, providing new insights into the differentiation of stem cell metabolism and fate trajectories.
Article
Biochemistry & Molecular Biology
Claudio Asencio, Thomas Schwarzl, Sudeep Sahadevan, Matthias W. Hentze
Summary: Small noncoding RNAs play important roles in cellular and organismal biology, working with RNA-binding proteins (RBPs). In order to specifically identify RBPs binding to small noncoding RNAs, a method called small noncoding RNA interactome capture (snRIC(2C)) was developed. Through this method, nearly 300 proteins that specifically bind to RNAs smaller than 200 nt in length (snRBPs) were identified, revealing differences from the total RNA-binding proteome. Further analysis showed that most glycolytic enzymes from yeast are snRBPs, and tRNA engagement of the glycolytic enzyme GAPDH is carbon source-dependent and regulated by the RNA polymerase III repressor Maf1, suggesting a regulatory interaction between glycolysis and RNA polymerase III activity. This study demonstrates the effectiveness of snRIC(2C) and other 2C-derived methods in studying RBPs and uncovering previously unrecognized interactions.
Article
Biochemistry & Molecular Biology
Edoardo Fatti, Alexander Hirth, Andrea Svorinic, Matthias Guenther, Gunter Stier, Cristina-Maria Cruciat, Sergio P. Acebron, Dimitris Papageorgiou, Irmgard Sinning, Jeroen Krijgsveld, Thomas Hoefer, Christof Niehrs
Summary: DDX RNA helicases not only promote RNA processing, but also activate multiple protein kinases, including CK1ε and CK2. It has been found that different DDX proteins can stimulate the kinase activity of CK2, and DDX1, DDX24, DDX41, and DDX54 are required for full kinase activity in vitro and in Xenopus embryos. Mathematical modeling and experimental evidence suggest that DDX proteins function as nucleotide exchange factors, reducing unproductive reaction intermediates and substrate inhibition in CK2-mediated protein kinase stimulation.
Article
Multidisciplinary Sciences
Joel I. Perez-Perri, Dunja Ferring-Appel, Ina Huppertz, Thomas Schwarzl, Sudeep Sahadevan, Frank Stein, Mandy Rettel, Bruno Galy, Matthias W. Hentze
Summary: The eRIC method was used to characterize the RNA-bound proteomes of three different mouse organs, revealing over 1300 active RNA-binding proteins, with nearly a quarter being previously unknown. Systematic differences in RNA binding were also observed between organs and cultured cells.
NATURE COMMUNICATIONS
(2023)
Article
Cardiac & Cardiovascular Systems
Eshita Varma, Jana Burghaus, Thomas Schwarzl, Thileepan Sekaran, Parul Gupta, Agnieszka A. Gorska, Christoph Hofmann, Claudia Stroh, Lonny Juergensen, Verena Kamuf-Schenk, Xue Li, Rebekka Medert, Florian Leuschner, Vivien Kmietczyk, Marc Freichel, Hugo A. Katus, Matthias W. Hentze, Norbert Frey, Mirko Voelkers
Summary: RNA-protein interactions are important for cardiac function, but the regulation of individual RNA-binding proteins through signaling cascades during heart failure development is not well understood. The study found that mTOR signaling is linked to the upregulation of the RNA-binding protein Ybx1, which is involved in cardiac hypertrophy by regulating protein synthesis. The depletion of Ybx1 preserved heart function during pathological cardiac hypertrophy.
BASIC RESEARCH IN CARDIOLOGY
(2023)
Article
Biochemical Research Methods
Sudeep Sahadevan, Thileepan Sekaran, Nadia Ashaf, Marko Fritz, Matthias W. Hentze, Wolfgang Huber, Thomas Schwarzl
Summary: Transcriptome-wide detection of binding sites of RNA-binding proteins can be achieved using Individual-nucleotide crosslinking and immunoprecipitation (iCLIP) and its derivative enhanced CLIP (eCLIP) sequencing methods. The python package htseq-clip is introduced for preprocessing, extracting, and summarizing crosslink site counts from i/eCLIP experimental data. The package provides crosslink site count matrices and other metrics for filtering and downstream analyses, such as the identification of differential binding sites.
Article
Biochemistry & Molecular Biology
Thomas Schwarzl, Sudeep Sahadevan, Benjamin Lang, Milad Miladi, Rolf Backofen, Wolfgang Huber, Matthias W. Hentze, Gian Gaetano Tartaglia
Summary: Enhanced crosslinking and immunoprecipitation sequencing (eCLIP-seq) is a method for detecting RNA-binding protein binding sites. However, current analysis strategies have low replication and high false positive rates. DEWSeq, a R/Bioconductor package, improves the detection of binding regions by utilizing replicate information and size-matched input controls. It has been shown to significantly increase the number and quality of binding sites.
NUCLEIC ACIDS RESEARCH
(2023)
Letter
Hematology
Silvia Colucci, Sandro Altamura, Oriana Marques, Katja Muedder, Anand R. Agarvas, Matthias W. Hentze, Martina U. Muckenthaler