Article
Oncology
Patrick C. O. 'Leary, Huadong Chen, Yagmur U. Doruk, Tess Williamson, Benjamin Polacco, Andrew S. McNeal, Tanushree Shenoy, Nupura Kale, Julia Carnevale, Erica Stevenson, David A. Quigley, Jonathan Chou, Felix Y. Feng, Danielle L. Swaney, Nevan J. Krogan, Minkyu Kim, Morgan E. Diolaiti, Alan Ashworth
Summary: Over one million cases of gastric cancer are diagnosed each year globally. A recent study found defects in the DNA damage response pathway in gastric tumors, creating therapeutic opportunities through synthetic lethal approaches. The study also discovered that ATR inhibitors can be used as targeted agents for gastric cancer and identified NMD proteins as potential biomarkers and therapeutic targets.
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
Paul J. J. Russell, Jacob A. A. Slivka, Elaina P. P. Boyle, Arthur H. M. Burghes, Michael G. G. Kearse
Summary: It is estimated that almost half of mammalian transcripts contain uORFs, which are smaller than the main ORF. uORFs are usually inhibitory but can allow for translation reinitiation. However, translation reinitiation after uORFs is not a reliable method to prevent NMD. The decision of whether NMD occurs after translating uORFs happens before reinitiation in mammalian cells.
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.
Article
Cell Biology
Gabriela Maria Guerra, Doreen May, Torsten Kroll, Philipp Koch, Marco Groth, Zhao-Qi Wang, Tang-Liang Li, Paulius Grigaravicius
Summary: SMG6 is an endonuclease that plays a crucial role in mRNA decay and is essential for neuroprogenitor cell differentiation. Its deletion results in perinatal lethality in mouse NPCs, affecting cell size, structure, and fate in a cell type-specific manner.
Article
Multidisciplinary Sciences
Edward J. Sanderlin, Melissa M. Keenan, Martin Mense, Alexey S. Revenko, Brett P. Monia, Shuling Guo, Lulu Huang
Summary: This study reveals that CFTR mRNAs with nonsense codons are predominantly degraded by the SMG6-mediated branch of the NMD pathway. This finding provides potential strategies for the treatment of cystic fibrosis.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Goncalo Nogueira, Rafael Fernandes, Juan F. Garcia-Moreno, Luisa Romao
Summary: <NMD has a dual role in cancer, with both pro-tumorigenic and anti-tumorigenic effects.>
<Advances in NMD research provide new perspectives on personalized cancer therapy.>
<Understanding the impact of NMD on tumor cells based on their genetic identity can lead to more effective personalized treatments.>
Article
Biology
Chengyan Chen, Yanmin Shen, Luqian Li, Yaoxin Ren, Zhao-Qi Wang, Tangliang Li
Summary: Nonsense-mediated mRNA decay (NMD) is a highly conserved regulatory mechanism in eukaryotic cells, and UPF3A and UPF3B are key factors in this process. This study found that UPF3A does not repress or promote NMD in mouse embryonic stem cells, somatic cells, and major organs when UPF3B is present.
LIFE SCIENCE ALLIANCE
(2023)
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)
Article
Biochemistry & Molecular Biology
Jianran Hu, Ping Li, Baozhong Shi, Jun Tie
Summary: Imp beta 1 plays a crucial role in NMD by interacting with UPF1 to regulate a wide range of target transcripts, affecting the interaction between UPF1 and other core factors, as well as their nuclear distribution.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Editorial Material
Plant Sciences
Yihan Dong, Lyubov A. Ryabova
Summary: In eukaryotes, mRNAs often have uORFs, which can inhibit the translation of the main ORF. In mammals, certain uORFs can trigger mRNA degradation through NMD. However, a study by Cymerman et al. (2023) shows that in Arabidopsis, uORFs with long and structured sequences do not induce mRNA degradation via NMD, in contrast to observations in mammals.
JOURNAL OF EXPERIMENTAL BOTANY
(2023)
Article
Plant Sciences
Miryam A. Cymerman, Helen Saul, Ronit Farhi, Karina Vexler, Dror Gottlieb, Irina Berezin, Orit Shaul
Summary: Translated upstream open reading frames (uORFs) can inhibit the translation of main open reading frames (ORFs) and lead to transcript degradation in eukaryotic cells. In mammalian cells, the length, structure, and reinitiation efficiency of translated uORFs play important roles in determining whether the transcripts will be targeted for degradation by the nonsense-mediated mRNA decay (NMD) pathway. However, the significance of these factors in NMD targeting for plants is still not well-studied.
JOURNAL OF EXPERIMENTAL BOTANY
(2023)
Article
Chemistry, Medicinal
Nesrine Benslimane, Federica Miressi, Camille Loret, Laurence Richard, Angelique Nizou, Ioanna Pyromali, Pierre-Antoine Faye, Frederic Favreau, Fabrice Lejeune, Anne-Sophie Lia
Summary: Nonsense mutations play a role in peripheral neuropathies by causing premature termination codons at the mRNA level. Readthrough molecules or NMD inhibitors, such as amlexanox, could be potential therapies for hereditary neuropathies. In the study, treatment with amlexanox on patient-derived neuronal cells carrying a specific mutation resulted in stabilization of GDAP1 mRNAs and restoration of mitochondrial morphology, highlighting the potential of readthrough molecules and NMD inhibitors for the treatment of genetic alterations in peripheral neuropathies.
Article
Multidisciplinary Sciences
Hanae Sato, Robert H. Singer
Summary: The author developed a single-cell reporter system to investigate cell-to-cell variability of NMD efficiency. The study revealed a wide range of NMD efficiency in different cells, potentially linked to the expression levels of surveillance factors.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Alexander C. Leeksma, Ingrid A. M. Derks, Brett Garrick, Aldo Jongejan, Martino Colombo, Timon Bloedjes, Torsten Trowe, Jim C. Leisten, Michelle Howarth, Mehnaz Malek, Deborah S. Mortensen, Kate Blease, Mathew C. Groza, Rama Krishna Narla, Remco Loos, Marie-Jose Kersten, Perry D. Moerland, Jeroen E. J. Guikema, Arnon P. Kater, Eric Eldering, Ellen H. Filvaroff
Summary: The study found that CC-115, in addition to its known targets TORK and DNA-PK, can also inhibit SMG1, a key regulator. CC-115 treatment increased SMG1-mediated NMD transcripts and showed sensitivity in certain cell lines like MM cell lines. It induced cell death through UPR transcripts and mitochondrial apoptosis, with superior antitumor activity compared to TORK inhibitors. These findings support further development of SMG1 inhibitors for MM therapy.
MOLECULAR ONCOLOGY
(2023)