Review
Biochemistry & Molecular Biology
Patricia Martins-Dias, Luisa Romao
Summary: Nonsense mutations can lead to dysfunctional proteins, but nonsense suppression therapy has the potential to restore protein function and treat a variety of genetic disorders. However, the efficiency of suppression may be influenced by nonsense-mediated decay, highlighting the importance of using NMD inhibitors or readthrough-compound potentiators to enhance therapeutic effects.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Mikel D. D. Ghelfi, Saleem Y. Y. Bhat, Hong Li, Barry S. S. Cooperman
Summary: The research findings show that Ataluren acts as a competitive inhibitor, blocking the catalytic function of the release factor complex (RFC) and inducing readthrough. This opens up the possibility of discovering new readthrough-inducing drugs that are both low in toxicity and more effective at stimulating readthrough.
Article
Multidisciplinary Sciences
Laure Bidou, Olivier Bugaud, Goulven Merer, Matthieu Coupet, Isabelle Hatin, Egor Chirkin, Sabrina Karri, Stephane Demais, Pauline Francois, Jean-Christophe Cintrat, Olivier Namy
Summary: In this study, a new drug was developed and evaluated for its clinical potential in treating genetic diseases caused by premature termination codons (PTCs). The drug, TLN468, was found to be more effective than the currently used gentamicin and acted on a broader range of sequences without affecting normal stop codon readthrough.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Soushi Kobayashi, Akira Kaji, Hideko Kaji
Summary: Eukaryotic elongation factor 3 (eEF3) stimulates the release of mRNA from puromycin-treated polysomes. When eEF3 is partially removed from the crude extract, a UAA stop codon readthrough occurs, leading to an increase in the downstream ORF product. eEF3 enhances the release of luciferase from polysomes by eukaryotic release factor (eRF)1 and eRF3. These findings suggest that eEF3 assists eRFs in performing normal protein synthesis termination in yeast.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Cell Biology
Lekha E. Manjunath, Anumeha Singh, Saubhik Som, Sandeep M. Eswarappa
Summary: This review discusses how recent technological and computational advances have increased our understanding of the stop codon readthrough process in the mammalian system. We propose transient molecular roadblocks as a possible mechanism for the induction of stop codon readthrough and argue that insights from natural readthrough events can guide the development of novel disease treatment strategies.
WILEY INTERDISCIPLINARY REVIEWS-RNA
(2023)
Article
Chemistry, Medicinal
Christie Morrill, Westley J. Friesen, Suresh Babu, Ramil Y. Baiazitov, Wu Du, Diane B. Karloff, Chang -Sun Lee, Young-Choon Moon, Hongyu Ren, Jairo Sierra, Yuki Tomizawa, Priya Vazirani, Ellen M. Welch, Xiaojiao Xue, Jin Zhuo
Summary: Using small molecules to induce readthrough is an effective method for treating genetic diseases and cancers. This study introduces a series of novel compounds that show potential for inducing readthrough in cells, either as combination therapy or standalone treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Venkateshwar Mutyam, Jyoti Sharma, Yao Li, Ning Peng, Jianguo Chen, Li Ping Tang, Emily Falk Libby, Ashvani K. Singh, Katja Conrath, Steven M. Rowe
Summary: Premature-termination codons (PTCs) in the CFTR gene lead to nonfunctional CFTR protein, accounting for 11% of CF-causing alleles with no current effective treatments. Novel CFTR correctors and potentiators show comparable effects to existing ones in vitro, and their combination can enhance the improvement of CFTR function with terminal PTC mutations.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Shan Li, Juan Li, Wenjing Shi, Ziyan Nie, Shasha Zhang, Fengdie Ma, Jun Hu, Jianjun Chen, Peiqiang Li, Xiaodong Xie
Summary: This review summarizes the pharmacodynamics and clinical application potential of the main translational readthrough-inducing drugs (TRIDs) discovered so far, especially some newly discovered TRIDs in the past decade. The discovery of these TRIDs brings hope for treating nonsense mutations in various genetic diseases. Further research is still needed to deeply understand the mechanism of eukaryotic cell termination and drug-induced PTC readthrough so that patients can achieve the greatest benefit from the various TRID treatments.
Article
Biochemistry & Molecular Biology
Maciej Dabrowski, Zuzanna Bukowy-Bieryllo, Claire L. Jackson, Ewa Zietkiewicz
Summary: The study identified several non-aminoglycoside compounds with potential to induce PTC-readthrough, which demonstrated minimal negative impact on cell viability and function compared to aminoglycosides, although with lower efficiency.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Roland N. Wagner, Michael Wiessner, Andreas Friedrich, Johanna Zandanell, Hannelore Breitenbach-Koller, Johann W. Bauer
Summary: This review summarizes the current understanding of translation termination and highlights newly discovered pathways that influence its fidelity. It also describes the mechanisms involved in the recognition and readthrough of premature termination codons (PTCs) and reports on compounds that induce PTC readthrough. The ongoing attempts of personalized nonsense suppression therapy in different disease contexts are also reviewed.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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
Genetics & Heredity
Sandra Luna, Leire Torices, Janire Mingo, Laura Amo, Isabel Rodriguez-Escudero, Pablo Ruiz-Ibarlucea, Asier Erramuzpe, Jesus M. Cortes, Maria I. Tejada, Maria Molina, Caroline E. Nunes-Xavier, Jose I. Lopez, Victor J. Cid, Rafael Pulido
Summary: The PTEN tumor suppressor gene is frequently mutated in tumors and in cancer predisposition patients or those with macrocephaly associated with autism. A study has analyzed PTEN nonsense mutations and set standards for the potential restoration of full-length PTEN proteins from mutated PTEN genes through translational readthrough. The findings indicate that prevalent pathogenic PTEN mutations can be functionally restored through readthrough-inducing compounds, offering potential for precision interventions in specific patient groups.
Article
Biochemistry & Molecular Biology
Daniel R. McHugh, Calvin U. Cotton, Craig A. Hodges
Summary: This study demonstrated synergy between NMD inhibitors and readthrough agents in increasing functional protein quantity following readthrough, suggesting a potential therapeutic option for treating nonsense mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Medicine, Research & Experimental
Federica Corrao, Maria Grazia Zizzo, Marco Tutone, Raffaella Melfi, Ignazio Fiduccia, Pietro Salvatore Carollo, Aldo Di Leonardo, Gaetano Caldara, Riccardo Perriera, Andrea Pace, Beatrice Belmonte, Selene Sammataro, Ivana Pibiri, Laura Lentini
Summary: This study investigated the acute toxicological effects of three Translational Readthrough Inducing Drugs (TRIDs) on mice and found that these drugs showed good tolerability without causing significant adverse effects in the mice.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Chemistry, Medicinal
Michael Popadynec, Alireza Baradaran-Heravi, Benjamin Alford, Scott A. Cameron, Keith Clinch, Jennifer M. Mason, Phillip M. Rendle, Olga Zubkova, Zhonghong Gan, Hui Liu, Oscar Rebollo, Dennis M. Whitfield, Fengyang Yan, Michel Roberge, David A. Powell
Summary: Aminoglycosides have the potential to induce readthrough of premature termination codons, which could be valuable in treating genetic diseases. Modification of aminoglycoside compounds to reduce cellular toxicity while maintaining readthrough activity is a strategy documented in this study.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
J. Jia, A. Furlan, S. Gonzalez-Hilarion, C. Leroy, D. C. Gruenert, D. Tulasne, F. Lejeune
CELL DEATH AND DIFFERENTIATION
(2015)
Article
Cell Biology
Jieshuang Jia, Elisabeth Werkmeister, Sara Gonzalez-Hilarion, Catherine Leroy, Dieter C. Gruenert, Frank Lafont, David Tulasne, Fabrice Lejeune
JOURNAL OF CELL SCIENCE
(2017)
Article
Multidisciplinary Sciences
Hana Benhabiles, Sara Gonzalez-Hilarion, Severine Amand, Christine Bailly, Anne Prevotat, Philippe Reix, Dominique Hubert, Eric Adriaenssens, Sylvie Rebuffat, David Tulasne, Fabrice Lejeune
Article
Cell Biology
Natacha Dreumont, Cyril F. Bourgeois, Fabrice Lejeune, Yilei Liu, Ingrid E. Ehrmann, David J. Elliott, James Stevenin
JOURNAL OF CELL SCIENCE
(2010)
Article
Genetics & Heredity
Sara Gonzalez-Hilarion, Terence Beghyn, Jieshuang Jia, Nadege Debreuck, Gonzague Berte, Kamel Mamchaoui, Vincent Mouly, Dieter C. Gruenert, Benoit Deprez, Fabrice Lejeune
ORPHANET JOURNAL OF RARE DISEASES
(2012)
Article
Multidisciplinary Sciences
Sebastien Apcher, Chrysoula Daskalogianni, Fabrice Lejeune, Benedicte Manoury, Gabriela Imhoos, Lea Heslop, Robin Fahraeus
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2011)
Article
Oncology
Adem Bokhari, Vincent Jonchere, Anais Lagrange, Romane Bertrand, Magali Syrcek, Laetitia Marisa, Olivier Buhard, Malorie Greene, Anastasia Demidova, Jieshuang Jia, Eric Adriaenssens, Thierry Chassat, Denis S. Biard, Jean-Francois Flejou, Fabrice Lejeune, Alex Duval, Ada Collura
Article
Multidisciplinary Sciences
Carole Trzaska, Severine Amand, Christine Bailly, Catherine Leroy, Virginie Marchand, Evelyne Duvernois-Berthet, Jean-Michel Saliou, Hana Benhabiles, Elisabeth Werkmeister, Thierry Chassat, Romain Guilbert, David Hannebique, Anthony Mouray, Marie-Christine Copin, Pierre-Arthur Moreau, Eric Adriaenssens, Andreas Kulozik, Eric Westhof, David Tulasne, Yuri Motorin, Sylvie Rebuffat, Fabrice Lejeune
NATURE COMMUNICATIONS
(2020)
Article
Biochemistry & Molecular Biology
Martine Palma, Catherine Leroy, Sophie Salome-Desnoulez, Elisabeth Werkmeister, Rebekah Kong, Marc Mongy, Herve Le Hir, Fabrice Lejeune
Summary: Nonsense-mediated mRNA decay (NMD) is a highly regulated quality control mechanism that degrades mRNAs containing premature termination codons. AKT1 kinase plays a crucial role in NMD by phosphorylating UPF1, which may have implications in cancer processes and therapy due to its overactivation in cancer cells.
NUCLEIC ACIDS RESEARCH
(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
Biotechnology & Applied Microbiology
Catherine Leroy, Sacha Spelier, Nadege Charlene Essonghe, Virginie Poix, Rebekah Kong, Patrick Gizzi, Claire Bourban, Severine Amand, Christine Bailly, Romain Guilbert, David Hannebique, Philippe Persoons, Gwenaelle Arhant, Anne Prevotat, Philippe Reix, Dominique Hubert, Michele Gerardin, Mathias Chamaillard, Natalia Prevarskaya, Sylvie Rebuffat, George Shapovalov, Jeffrey Beekman, Fabrice Lejeune
Summary: DAP can correct nonsense mutations in genetic diseases, restore gene function, and has therapeutic potential.
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
Fabrice Lejeune