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
Medicine, Research & Experimental
Sara H. Osum, Eunice I. Oribamise, Stanislas M. A. S. Corbiere, Mandy Taisto, Tyler Jubenville, Alex Coutts, Mark N. Kirstein, James Fisher, Christopher Moertel, Ming Du, David Bedwell, David A. Largaespada, Adrienne L. Watson
Summary: Neurofibromatosis type 1 (NF1) is caused by germline mutations in the tumor-suppressor gene NF1, leading to an increased risk of nervous system tumors. In this study, a minipig model of NF1 carrying a premature termination codon (PTC) was used to investigate the potential of nonsense suppression in restoring expression of the NF1-encoded protein neurofibromin. The results showed that nonsense suppression did not significantly increase neurofibromin in primary NF1-'- Schwann cells, but it reduced phosphorylated ERK.
MOLECULAR THERAPY-NUCLEIC ACIDS
(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
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.
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.
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
Biochemistry & Molecular Biology
Kyle T. Powers, Flint Stevenson-Jones, Sathish K. N. Yadav, Beate Amthor, Joshua C. Bufton, Ufuk Borucu, Dakang Shen, Jonas P. Becker, Daria Lavysh, Matthias W. Hentze, Andreas E. Kulozik, Gabriele Neu-Yilik, Christiane Schaffitzel
Summary: The study shows that BIaS inhibits translation elongation and termination in mammals by distorting the 3'CCA tail of the P-site tRNA and interfering with the accommodation of eRF1 into the peptidyl transferase center. Additionally, BIaS inhibits nonsense-mediated mRNA decay and modulates translation dynamics at premature termination codons in human cells.
NUCLEIC ACIDS RESEARCH
(2021)
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
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)
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
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
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
Biochemistry & Molecular Biology
Ana Rita Marques, Joao Xavier Santos, Hugo Martiniano, Joana Vilela, Celia Rasga, Luisa Romao, Astrid Moura Vicente
Summary: This study investigates the role of the Nonsense-Mediated mRNA Decay (NMD) pathway in Autism Spectrum Disorder (ASD) and identifies many genetic variants associated with NMD genes in ASD patients, suggesting a potential involvement of NMD in ASD pathophysiology.
Article
Chemistry, Organic
Adesh Kumar Singh, Rapelly Venkatesh, Vimlesh Kumar Kanaujiya, Varsha Tiwari, Jeyakumar Kandasamy
Summary: An efficient method for the synthesis of C-1 aryl enones from aryl iodides and glycal enones through palladium-catalyzed cross-coupling reactions under ligand-free conditions was developed. This method is applicable to a wide range of aryl iodides with different electron-donating and withdrawing groups, and can be carried out under mild reaction conditions.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Genetics & Heredity
Ashlee Long, Hui Liu, Jian Liu, Michael Daniel, David M. Bedwell, Bruce Korf, Robert A. Kesterson, Deeann Wallis
Summary: This study investigates the functional consequences of 29 NF1 variant cDNAs, revealing variant-specific differences in neurofibromin protein levels and Ras signaling activity. The findings suggest that some variants may lead to NF1 gene or protein instability, while others may not functionally engage Ras. These assays could aid in categorizing variants by their effects and have potential implications for more targeted therapeutics in the future.
Article
Chemistry, Organic
Sadaf Azeez, Popuri Sureshbabu, Shahulhameed Sabiah, Jeyakumar Kandasamy
Summary: A practical method for the reduction of activated primary and secondary amides into aldehydes using DIBAL-H in toluene is disclosed. This method exhibits broad substrate scope, good functional group compatibility, and quick conversions.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Organic
Rapelly Venkatesh, Gauri Shankar, Aswathi C. Narayanan, Gyan Modi, Shahulhameed Sabiah, Jeyakumar Kandasamy
Summary: This study describes a multicomponent synthesis of biologically active S-benzyl dithiocarbamates using para-quinone methides, amines, and carbon disulfide under catalyst and additive-free conditions. The reactions proceed rapidly at room temperature with high yields. One of the synthesized compounds, compound 3, exhibits significant acetylcholinesterase inhibition and antioxidant activity at low concentrations.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Vimlesh Kumar Kanaujiya, Varsha Tiwari, Siddharth Baranwal, Vandana Srivastava, Jeyakumar Kandasamy
Summary: A convenient and practical method for denitrosation of aryl-N-nitrosamines using ethanethiol and PTSA under mild reaction conditions is reported. The reactions occur at room temperature, yielding amines in good to excellent yields. This method exhibits stability of many reducible functional groups during denitrosation, and features a broad substrate scope and easy operations.
Article
Physiology
Jianguo Chen, Kari Thrasher, Lianwu Fu, Wei Wang, Soheil Aghamohammadzadeh, Hui Wen, Liping Tang, Kim M. Keeling, Emily Falk Libby, David M. Bedwell, Steven M. Rowe
Summary: In this study, it was found that G550X-CFTR patient-derived intestinal organoids had significantly higher swelling after treatment with ELX-02 compared to G542X-CFTR organoids. Tryptophan was the only amino acid inserted in the G550X position after readthrough. The resulting G550W-CFTR protein exhibited supernormal CFTR activity, PKA sensitivity, and open probability. These results indicate that aminoglycoside-induced readthrough of G550X produces greater CFTR function due to the gain-of-function properties of the CFTR readthrough product.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2023)
Article
Chemistry, Medicinal
Parmanand Ahirwar, Veronika Kozlovskaya, Bhavitavya Nijampatnam, Edwin M. Rojas, Piyasuda Pukkanasut, Daniel Inman, Maksim Dolmat, Anna C. Law, Norbert Schormann, Champion Deivanayagam, Gregory J. Harber, Suzanne M. Michalek, Hui Wu, Eugenia Kharlampieva, Sadanandan E. Velu
Summary: We developed analoguesof biofilm inhibitor IIIC5 to enhance solubility, maintain inhibitory activities, and facilitate encapsulation into pH-responsive hydrogel microparticles. The optimized compound HA5 exhibited improved solubility (120.09 μg/mL), inhibited Streptococcus mutans biofilm formation with an IC50 value of 6.42 μM, and showed no adverse effects on the growth of oral commensal species even at a 15-fold higher concentration. The crystal structure of HA5 in complex with GtfB catalytic domain unveiled its active site interactions. HA5 demonstrated its ability to inhibit S. mutans Gtfs and reduce glucan production. Encapsulating HA5 in hydrogel to form hydrogel-encapsulated biofilm inhibitor (HEBI) achieved selective inhibition of S. mutans biofilms similar to HA5. Treatment of S. mutans-infected rats with HA5 or HEBI resulted in a significant reduction in buccal, sulcal, and proximal dental caries compared to untreated infected rats.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Organic
Shweta Singh, Jeyakumar Kandasamy
Summary: Acyl hydrazides can be synthesized from amides at room temperature through N-activation reactions. A wide range of functionalized primary and secondary amides were transformed into N-Boc, N-nitroso, and N-tosyl amides, which were then subjected to transamidation with hydrazine hydrate to yield the desired acyl hydrazides in yields of 76-94%. The developed methodology has the advantages of broad substrate scope, shorter reaction time, and mild reaction conditions.
ASIAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Huiya Yang, Robert H. Brown, Dan Wang, Kevin A. Strauss, Guangping Gao
Summary: GM3 synthase deficiency (GM3SD) is a genetic disorder caused by mutations in the ST3GAL5 gene, leading to neurological impairment. Recombinant adeno-associated viruses (rAAVs) can be used as a therapeutic strategy to restore gene expression and normalize gangliosides in the brain. The use of a second-generation vector with CNS-restricted expression of ST3GAL5 showed promising results in rescuing lethality and improving behavior in GM3SD mice.
Article
Biochemistry & Molecular Biology
Aswathi C. Narayanan, Rapelly Venkatesh, Shweta Singh, Gourav Singh, Gyan Modi, Sundaram Singh, Jeyakumar Kandasamy
Summary: The synthesis of trans-cinnamic acid containing phenylethanoid glycosides was achieved through palladium-catalyzed cross-coupling reactions. The reactions proceeded at room temperature without the need for additives or base. The obtained products showed good to excellent yields and compound 16 exhibited significant inhibitory activities against BChE and AChE enzymes, suggesting potential anti-Alzheimer activity.
CARBOHYDRATE RESEARCH
(2023)
Article
Chemistry, Organic
Nitin Kumar, Rapelly Venkatesh, Sundaram Singh, Jeyakumar Kandasamy
Summary: An efficient and eco-friendly method has been developed for preparing functionalized 3-(S)-arylthioindoles from indoles and aryl thiols in water, achieving good to excellent yields. The reaction is catalyzed by K2S2O8 in the presence of glucose at room temperature. The developed methodology exhibits broad substrate scope, high functional group tolerance, room temperature reactions, and metal-free conditions.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Adesh Kumar Singh, Rapelly Venkatesh, Jeyakumar Kandasamy
Summary: In this study, the 1,4-conjugate addition of arylboronic acids to glycal enones was successfully achieved, leading to the synthesis of 2-deoxy-alpha-aryl-C-glycosides. Various glycal enones derived from different sugars participated in the coupling reaction with different arylboronic acids smoothly, and different protecting groups were found to be compatible under optimized conditions.
SYNTHESIS-STUTTGART
(2023)
Article
Energy & Fuels
Achayalingam Ramesh, Sourabh Basu, Vellaichamy Ganesan, Pawan Kumar Soni, Shanmugam Manivannan, Jeyakumar Kandasamy, Michael Sterlin Leo Hudson, Mohammad Abu Shaz
Summary: In this study, two-dimensional carbon nanosheets derived from biomass precursor were successfully synthesized through a cost-effective salt-templated process. The thickness and capacitance of the nanosheets were altered by adjusting the carbon precursor to salt-template ratio. Thinner carbon nanosheets exhibited superior electrochemical properties and capacitance compared to thicker ones, without the need for chemical activation.
Article
Medicine, Research & Experimental
Hao Chang, Ailing Du, Jun Jiang, Lingzhi Ren, Nan Liu, Xuntao Zhou, Jialing Liang, Guangping Gao, Dan Wang
Summary: This article explores the potential of gene therapy using genetically engineered recombinant adeno-associated virus (rAAV). By incorporating a non-canonical amino acid (ncAA) into the AAV5 capsid, researchers discovered that the modified viruses had higher transduction efficiency, and one specific virus showed enhanced lung-specific transduction in mice. Structural modeling suggests that the unique structure of the ncAA may impact key structures on the virus capsid surface, thus modulating vector transduction. The results of this study indicate that incorporating ncAAs into AAV capsids may play an important role in gene therapy vector discovery.
MOLECULAR THERAPY METHODS & CLINICAL DEVELOPMENT
(2023)
Article
Chemistry, Organic
Nitin Kumar, Rapelly Venkatesh, Jeyakumar Kandasamy
Summary: We report a triflic acid promoted multi-component synthesis of functionalized S-benzyl dithiocarbamates from diazo compounds, carbon disulfide and secondary amines. The reactions proceed at room temperature and give good yields. The important features of this methodology are its wide-substrate scope and easy operation.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
