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.
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
Biology
Martine Palma, Fabrice Lejeune
Summary: Recognition of the stop codon is crucial for terminating translation and synthesizing the correct size protein. Stop codon readthrough can occur under specific conditions, leading to different protein isoforms, and has potential therapeutic implications for genetic diseases caused by nonsense mutations.
BIOLOGICAL REVIEWS
(2021)
Article
Biochemistry & Molecular Biology
Ze Liu, Justin Wang, Yi Shi, Brian A. Yee, Markus Terrey, Qian Zhang, Jenq-Chang Lee, Kuo- Lin, Andrew H-J Wang, Susan L. Ackerman, Gene W. Yeo, Haissi Cui, Xiang-Lei Yang
Summary: Translational readthrough of UGA stop codons by selenocysteine-specific tRNA enables the synthesis of selenoproteins. In addition, this mechanism can also increase translational readthrough of non-selenocysteine genes to create C-terminally extended isoforms. The recognition of target mRNAs by seryl-tRNA synthetase is dependent on its enzymatic activity and a vertebrate-specific domain. The findings expand our understanding of selenoprotein biosynthesis and suggest a potential avenue for therapeutic targeting of nonsense mutations using endogenous factors.
NUCLEIC ACIDS RESEARCH
(2023)
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
Multidisciplinary Sciences
Jyoti Sharma, Ming Du, Eric Wong, Venkateshwar Mutyam, Yao Li, Jianguo Chen, Jamie Wangen, Kari Thrasher, Lianwu Fu, Ning Peng, Liping Tang, Kaimao Liu, Bini Mathew, Robert J. Bostwick, Corinne E. Augelli-Szafran, Hermann Bihler, Feng Liang, Jerome Mahiou, Josef Saltz, Andras Rab, Jeong Hong, Eric J. Sorscher, Eric M. Mendenhall, Candice J. Coppola, Kim M. Keeling, Rachel Green, Martin Mense, Mark J. Suto, Steven M. Rowe, David M. Bedwell
Summary: In this study, compounds with readthrough activity were identified and shown to reduce premature termination associated with cystic fibrosis by lowering eRF1 levels. These compounds, including SRI-41315 and SRI-37240, have potential as promising treatment strategies for diseases caused by PTCs.
NATURE COMMUNICATIONS
(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
Medicine, Research & Experimental
Rhianna E. Lee, Catherine A. Lewis, Lihua He, Emily C. Bulik-Sullivan, Samuel C. Gallant, Teresa M. Mascenik, Hong Dang, Deborah M. Cholon, Martina Gentzsch, Lisa C. Morton, John T. Minges, Jonathan W. Theile, Neil A. Castle, Michael R. Knowles, Adam J. Kimple, Scott H. Randell
Summary: Cell lines created by overexpression of Bmi-1 and hTERT can faithfully mimic the response of primary airway epithelial cells to CFTR modulators in individuals with cystic fibrosis (CF). The therapeutic approach using Cereblon E3 ligase modulators targeting eukaryotic release factor 3a (eRF3a) can rescue CFTR nonsense mutations and also diminish epithelial sodium channel (ENaC) function.
JOURNAL OF CLINICAL INVESTIGATION
(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)
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
Alireza Baradaran-Heravi, Aruna D. Balgi, Sara Hosseini-Farahabadi, Kunho Choi, Cristina Has, Michel Roberge
Summary: Premature termination codon (PTC) readthrough is a potential treatment for genetic diseases caused by nonsense mutations. Aminoglycosides induce low levels of PTC readthrough but are toxic. Finding compounds to enhance PTC readthrough by aminoglycosides or reduce toxicity remains a challenge.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Mohammed Hafeezunnisa, Passong Immanual R. Chhakchhuak, Janani Krishnakumar, Ranjan Sen
Summary: The Rho-dependent transcription termination in bacteria specifically controls the expression of toxin-antitoxin modules of cryptic prophages in E. coli, enhancing bacterial innate immunity. However, this mechanism does not regulate most chromosomal TA modules.
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
Pouire Yameogo, Benjamin L. Duchene, Nathalie Majeau, Jacques P. Tremblay
Summary: CRISPR/Cas9 has opened up opportunities for genetic mutation correction therapies, yet long-term expression of the Cas9 gene can lead to off-target mutations and immune responses. A drug-inducible system was proposed to limit the expression of Cas9 nuclease. Through introducing a premature termination codon (PTC) and treatment with an aminoglycoside drug, it was demonstrated that Cas9 protein expression can be controlled effectively.
Article
Biochemistry & Molecular Biology
Olga Kyrchanova, Vladimir Sokolov, Maxim Tikhonov, Galya Manukyan, Paul Schedl, Pavel Georgiev
Summary: In higher eukaryotes, the organization of enhancer-promoter interactions is regulated by topologically associated domains, tethering elements, and chromatin insulators/boundaries. The mechanisms controlling the functions of insulators/boundaries are not well understood. This study focuses on the potential impact of readthrough transcription (RT) on boundary function using the Drosophila bithorax complex (BX-C) as a model system. The results show that RT can interfere with boundary activity, suggesting that it may be a commonly used mechanism to regulate boundary function and gene expression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Jingwen Wang, Bingnan Li, Sueli Marques, Lars M. Steinmetz, Wu Wei, Vicent Pelechano
NUCLEIC ACIDS RESEARCH
(2020)
Article
Cell Biology
Francesca Briganti, Han Sun, Wu Wei, Jingyan Wu, Chenchen Zhu, Martin Liss, Ioannis Karakikes, Shannon Rego, Andrea Cipriano, Michael Snyder, Benjamin Meder, Zhenyu Xu, Gilles Millat, Michael Gotthardt, Mark Mercola, Lars M. Steinmetz
Article
Biochemistry & Molecular Biology
Victoria Begley, Antonio Jordan-Pla, Xenia Penate, Ana Garrido-Godino, Drice Challal, Abel Cuevas-Bermudez, Adria Mitjavila, Mara Barucco, Gabriel Gutierrez, Abhyudai Singh, Paula Alepuz, Francisco Navarro, Domenico Libri, Jose E. Perez-Ortin, Sebastian Chavez
Summary: The study demonstrated significant effects of Xrn1 perturbation on transcription elongation through changes in RNA Pol II profiles and nucleosome mapping in Saccharomyces cerevisiae. Additionally, accumulation of RNA Pol II upstream of polyadenylation sites was detected, suggesting a connection between mRNA decay and late transcription elongation. These findings indicate that Xrn1 influences transcription elongation through multiple mechanisms.
Article
Biology
Kristen L. Wells, Corey N. Miller, Andreas R. Gschwind, Wu Wei, Jonah D. Phipps, Mark S. Andersonz, Lars M. Steinmetz
Article
Biochemistry & Molecular Biology
Umberto Aiello, Drice Challal, Griselda Wentzinger, Armelle Lengronne, Rowin Appanah, Philippe Pasero, Benoit Palancade, Domenico Libri
Summary: Cellular homeostasis requires the coordination of several machineries, including the Sen1 helicase which terminates non-coding transcription. This study shows that Sen1 plays a key regulatory role in resolving transcription conflicts and R-loops, thus maintaining genome stability.
Article
Biochemistry & Molecular Biology
Jeremy Scutenaire, Damien Plassard, Melody Matelot, Tommaso Villa, Julie Zumsteg, Domenico Libri, Bertrand Seraphin
Summary: This study investigates the role of m(6)A modification in meiosis. Using the yeast Saccharomyces cerevisiae, the researchers identified Pho92 as an important m(6)A reader that facilitates meiotic progression by promoting the down-regulation of specific mRNAs in a m(6)A-dependent manner.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Juanjuan Xie, Umberto Aiello, TYves Clement, Nouhou Haidara, Mathias Girbig, Jana Schmitzova, Vladimir Penal, Christoph W. Mueller, Domenico Libri, Odil Porrua
Summary: RNA polymerase III utilizes multiple mechanisms, including the recognition of T-tracts, the secondary structure of nascent RNAs, and the helicase Sen1, to ensure efficient transcription termination.
Article
Multidisciplinary Sciences
Laura Matabishi-Bibi, Drice Challal, Mara Barucco, Domenico Libri, Anna Babour
Summary: Cellular homeostasis is maintained by surveillance mechanisms that intervene at virtually every step of gene expression. The yeast chromatin remodeler Isw1 restricts the nuclear export of mature mRNA ribonucleoparticles, and directly binds to the 3' untranslated region of HAC1 mRNA to limit its nuclear export and ensure accurate unfolded protein response (UPR) attenuation.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Mathias Girbig, Juanjuan Xie, Helga Groetsch, Domenico Libri, Odil Porrua, Christoph W. Mueller
Summary: RNA polymerase III terminates transcription by forming a hydrogen-bond network with the poly(dT) region on the non-template strand, as revealed by cryoelectron microscopy. The study also shows that the subcomplex C53-C37 indirectly participates in Pol III termination.
Article
Cell Biology
Juanjuan Xie, Domenico Libri, Odil Porrua
Summary: Transcription termination is an essential step in the transcription process, allowing the release of transcripts and recycling of the polymerase. It is crucial for preventing interference between neighboring transcription units and conflicts with other DNA-associated processes. This review discusses the mechanisms of transcription termination by different classes of eukaryotic RNAPs and highlights interesting commonalities.
JOURNAL OF CELL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Jonathan Heuze, Samira Kemiha, Antoine Barthe, Alba Toran Vilarrubias, Elyes Aouadi, Umberto Aiello, Domenico Libri, Yea-Lih Lin, Armelle Lengronne, Jerome Poli, Philippe Pasero
Summary: R-loops, RNA:DNA hybrids, act as barriers to replication forks and interfere with postreplicative fork repair mechanisms if not promptly degraded by RNase H. Cells lacking RNase H exhibit impaired replication under challenging conditions, and triptolide, an inhibitor of transcription, restores fork resection.
Article
Genetics & Heredity
Sibylle C. Vonesch, Shengdi Li, Chelsea Szu Tu, Bianca P. Hennig, Nikolay Dobrev, Lars M. Steinmetz
Summary: The study presents a highly scalable method for preparing high-quality whole-genome sequencing libraries directly from Saccharomyces cerevisiae cultures in less than 3 hours at 34 cents per sample. By skipping the step of genomic DNA extraction, adding a nucleosome release step, and enriching PCR, the resulting libraries show even genomic coverage and quality comparable to commercially available kits. This protocol enables rapid preparation of unbiased and high-quality sequencing libraries for hundreds of yeast strains in a single day at a low price.
G3-GENES GENOMES GENETICS
(2021)
Article
Multidisciplinary Sciences
Tommaso Villa, Yan Jaszczyszyn, Domenico Libri
Summary: The Nrd1-Nab3-Sen1 (NNS) complex in yeast cells plays a crucial role in directing transcription termination of ncRNA genes and promoting the degradation of pervasive transcripts. Inhibition of the exosome leads to accumulation of ncRNAs and disruption of NNS targeting mechanisms. Expression of a circular RNA decoy effectively sequesters Nab3, leading to decreased binding on NNS targets and genomewide termination impairment.
Article
Biochemistry & Molecular Biology
Jay W. Schneider, Saji Oommen, Muhammad Y. Qureshi, Sean C. Goetsch, David R. Pease, Rhianna S. Sundsbak, Wei Guo, Mingming Sun, Han Sun, Hidehito Kuroyanagi, Dennis A. Webster, Alexander W. Coutts, Kimberly A. Holst, Brooks S. Edwards, Nikolas Newville, Matthew A. Hathcock, Tamene Melkamu, Francesca Briganti, Wu Wei, Maria G. Romanelli, Scott C. Fahrenkrug, Doug E. Frantz, Timothy M. Olson, Lars M. Steinmetz, Daniel F. Carlson, Timothy J. Nelson
Article
Materials Science, Biomaterials
Semih Calamak, Menekse Ermis, Han Sun, Saiful Islam, Michael Sikora, Michelle Nguyen, Vasif Hasirci, Lars M. Steinmetz, Utkan Demirci
ADVANCED BIOSYSTEMS
(2020)