Article
Cell Biology
Lilas Alboushi, Angela P. Hackett, Parisa Naeli, Mostafa Bakhti, Seyed Mehdi Jafarnejad
Summary: Cancer cells require excessive mRNA translation and protein synthesis but can be inhibited by unfavorable conditions. To survive and gain a proliferative advantage, cancer cells adapt to stresses by employing specialized translation mechanisms.
CELLULAR SIGNALLING
(2021)
Review
Biochemistry & Molecular Biology
Qiushuang Wu, Ariel A. Bazzini
Summary: Messenger RNA (mRNA) stability and translational efficiency play crucial roles in protein production. Recent studies have shown that ribosomes, in addition to protein synthesis, also control mRNA stability in a codon-dependent manner known as codon optimality. Codons have a significant impact on mRNA stability and provide cis-regulatory information beyond their encoding amino acids. The molecular mechanism of codon optimality is still not fully understood, but it appears that the translation elongation rate triggers mRNA decay, where transfer RNAs may serve as master gene regulators influencing mRNA stability. This article discusses the findings of codon optimality and gene regulation related to codon composition in different eukaryotic species.
ANNUAL REVIEW OF BIOCHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Markus Hopfler, Ramanujan S. Hegde
Summary: Cells regulate mRNA processing, localization, and stability to ensure accurate gene expression. Recent discoveries have uncovered co-translational mechanisms that modulate mRNA translation, localization, processing, and stability. These mechanisms operate by recognizing the nascent protein and directing mRNA fate, allowing cells to dynamically regulate their transcriptomes in response to cellular changes.
Article
Biochemistry & Molecular Biology
Jasmin Hertler, Kaouthar Slama, Benedikt Schober, Zeynep Ozrendeci, Virginie Marchand, Yuri Motorin, Mark Helm
Summary: Techniques have been developed to isolate long, translatable, and internally point-modified mRNA, enabling functional analysis of these modified mRNAs.
NUCLEIC ACIDS RESEARCH
(2022)
Review
Biochemistry & Molecular Biology
Joanna R. Kovalski, Duygu Kuzuoglu-Ozturk, Davide Ruggero
Summary: This review discusses how cancer cells regulate protein expression through translational control and highlights the clinical potential of targeting translation factors as anti-cancer therapies. It also details the interaction between RNA sequence and structural elements, the translational machinery, and RNA-binding proteins in coordinating specific pro-survival and pro-growth programs. Additionally, the review provides an overview of current and emerging technologies for studying selective translational control in cancer cells and the tumor microenvironment.
Article
Biochemistry & Molecular Biology
Shir Bahiri Elitzur, Rachel Cohen-Kupiec, Dana Yacobi, Larissa Fine, Boaz Apt, Alon Diament, Tamir Tuller
Summary: The Shine-Dalgarno model indicates that translation initiation in bacteria is regulated by rRNA-mRNA interactions. These interactions not only affect the initiation phase of translation, but also influence all steps of the translation process, including pre-initiation, initiation, elongation, and termination. The study suggests that these interactions play a crucial role in shaping the evolution of transcripts in bacteria by impacting translation efficiency.
Article
Multidisciplinary Sciences
Chiara Pederiva, Davide M. Trevisan, Dimitra Peirasmaki, Shan Chen, Sharon A. Savage, Ola Larsson, Jernej Ule, Laura Baranello, Federico Agostini, Marianne Farnebo
Summary: Posttranscriptional modifications of mRNA, including pseudouridylation, play a crucial role in gene expression regulation. In this study, dyskerin, a pseudouridine synthase, was found to bind to RNA polymerase II and be responsible for pseudouridylation of thousands of mRNAs. Dyskerin-mediated pseudouridylation was shown to interfere with translation and reduction of the modification led to enhanced protein synthesis. Furthermore, dyskeratosis congenita patients with mutations in the dyskerin-encoding gene showed severe reduction in mRNA pseudouridylation.
Article
Multidisciplinary Sciences
Sameer Aryal, Francesco Longo, Eric Klann
Summary: Through ribosome profiling and RNA sequencing, we found reduced ribosome footprint abundance in the majority of differentially translated genes in FXS mice, which can be corrected by genetic reduction of S6K1. Additionally, genetic removal of S6K1 prevented alterations in translation efficiencies with coding sequence length across mRNAs in FXS mouse cortices.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Chemistry, Multidisciplinary
Florian P. Weissenboeck, Helena Schepers, Andrea Rentmeister
Summary: A major stage in gene expression is mRNA translation, and the regulation of this process is crucial for cellular protein production. Spatial and temporal control of gene expression is especially evident in polar cells and embryonic development. External bioorthogonal triggers are useful tools to dissect the complex processes and understand the underlying links, particularly in cases of malfunction. Equipping nucleic acids with light-responsive groups has been an effective approach to examine the dynamic regulation of mRNA translation in living cells. This review provides an overview of recent methods for optochemically controlling translation, with a focus on cis-acting technologies.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Cell Biology
Xiaoxiao Ouyang, Xueyun Wang, Pan Li, Qin Huang, Li Zhou, Jingxiang Li, Li Gao, Qi Sun, Fangni Chai, Shupan Guo, Zhihui Zhou, Xin Liu, Lunzhi Dai, Wei Cheng, Haiyan Ren
Summary: In this study, the host protein ZPR1 was identified as an interacting partner of the EPEC effector NleE through protein crosslinking. It was found that ZPR1 regulates CHOP-mediated UPRER at the transcriptional level through liquid-liquid phase separation. Interestingly, NleE disrupts the binding ability of ZPR1 with K63-ubiquitin chains, which promotes its liquid-liquid phase separation. Further analysis showed that EPEC restricts host UPRER pathways at the transcription level in a cascade-dependent manner between NleE and ZPR1. Overall, this study reveals the mechanism by which EPEC interferes with CHOP-UPRER through regulating ZPR1 to facilitate immune evasion.
Article
Biochemistry & Molecular Biology
Sebastian Filbeck, Federico Cerullo, Helge Paternoga, George Tsaprailis, Claudio A. P. Joazeiro, Stefan Pfeffer
Summary: The study found that aborted translation leads to large ribosomal subunits obstructed with tRNA-linked nascent chains, which are substrates of ribosome-associated quality control. Bacterial RqcH, a widely conserved RQC factor, can modify the C-termini of nascent chains to form a polyalanine degron. The research revealed the mechanism of tRNA selection and the role of RqcH in the synthesis of nascent chains.
Article
Biochemistry & Molecular Biology
Elodie Villa, Umakant Sahu, Brendan P. O'Hara, Eunus S. Ali, Kathryn A. Helmin, John M. Asara, Peng Gao, Benjamin D. Singer, Issam Ben-Sahra
Summary: mTORC1 regulates m(6)A RNA modification by controlling MAT2A and WTAP levels to promote protein synthesis and cell growth.
Article
Biochemistry & Molecular Biology
Yann Tardivat, Piotr Sosnowski, Antonin Tidu, Eric Westhof, Gilbert Eriani, Franck Martin
Summary: The non-structural protein NSP1 in SARS-CoV-2 inhibits the translation of host mRNAs by binding to the ribosome's mRNA entry channel. It also cleaves both host and viral mRNAs in the 5' UTR, with different patterns of cleavage observed. The cleavage positions in host mRNAs depend on their proximity to the 5' cap, while SARS-CoV-2 RNAs have specific cleavage positions at high NSP1 concentrations.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Aleksandra E. Korenskaia, Yury G. Matushkin, Sergey A. Lashin, Alexandra Klimenko
Summary: This study evaluates the correlation between experimentally measured protein abundance and predicted translation elongation efficiency characteristics for 26 prokaryotes. Results show that, for some organisms, secondary structures are better predictors of protein abundance than codon usage bias. Several factors, including elongation efficiency optimization type, taxonomical identity, and growth rate, are associated with the value of the correlation coefficient.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Danielle M. Garshott, Heeseon An, Elayanambi Sundaramoorthy, Marilyn Leonard, Alison Vicary, J. Wade Harper, Eric J. Bennett
Summary: Post-translational modification of ribosomal proteins plays a crucial role in regulating protein biogenesis, with specific ubiquitylation events on 40S ribosomal proteins identified. The study also uncovers the regulatory mechanisms of the ubiquitylation of uS3 and uS5 proteins, as well as the initiation RQC pathway (iRQC) that modulates translation activity on 40S ribosomes during translation initiation.
Article
Chemistry, Analytical
Nicole Strittmatter, Frances M. Richards, Alan M. Race, Stephanie Ling, Daniel Sutton, Anna Nilsson, Yann Wallez, Jennifer Barnes, Gareth Maglennon, Aarthi Gopinathan, Rebecca Brais, Edmond Wong, Maria Paola Serra, James Atkinson, Aaron Smith, Joanne Wilson, Gregory Hamm, Timothy Johnson, Charles R. Dunlop, Brajesh P. Kaistha, Josephine Bunch, Owen J. Sansom, Zoltan Takats, Per E. Andren, Alan Lau, Simon T. Barry, Richard J. A. Goodwin, Duncan Jodrell
Summary: Gemcitabine distribution and metabolism were assessed using a multimodal imaging approach, revealing that active metabolites primarily reached tumor cell compartments, while an ATR inhibitor targeted nonviable tumor regions.
ANALYTICAL CHEMISTRY
(2022)
Article
Biotechnology & Applied Microbiology
Tanya J. Knight, Jane F. Povey, Davide Vito, Atul Mohindra, Colin M. Jaques, C. Mark Smales
Summary: In this study, the site of fragmentation of a model immunoglobulin G1 Fc-fusion protein was identified, and the observed clipping and aggregation were reduced by lowering the temperature and adding chemical reagents. The findings suggest that manipulating mRNA translation can improve protein folding and reduce the susceptibility to fragmentation.
BIOTECHNOLOGY AND BIOENGINEERING
(2022)
Editorial Material
Cell Biology
Owen Sansom
Summary: Over the past 20 years, the UK has excelled in generating and utilizing complex mouse models for the investigation of human disease. However, there is still a need to improve the translation of animal research into clinical benefits. The new UK Medical Research Council (MRC) National Mouse Genetics Network aims to address this challenge by fostering collaborations between basic scientists and clinicians. This network will have a significant impact on harnessing recent advances in mouse genetics.
DISEASE MODELS & MECHANISMS
(2022)
Article
Food Science & Technology
Stephanie May, Kirsty R. Greenow, Adam T. Higgins, Anna Derrick, Elaine Taylor, Pan Pan, Maria Konstantinou, Colin Nixon, Thomas E. Wooley, Owen J. Sansom, Li-Shu Wang, Lee Parry
Summary: Black raspberries have a protective effect on normal and mutant intestinal stem cells, and can prevent the occurrence of colorectal cancer.
MOLECULAR NUTRITION & FOOD RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Victor H. Villar, Maria Francesca Allega, Ruhi Deshmukh, Tobias Ackermann, Mark A. Nakasone, Johan Vande Voorde, Thomas M. Drake, Janina Oetjen, Algernon Bloom, Colin Nixon, Miryam Muller, Stephanie May, Ee Hong Tan, Lars Vereecke, Maude Jans, Gillian Blancke, Daniel J. Murphy, Danny T. Huang, David Y. Lewis, Thomas G. Bird, Owen J. Sansom, Karen Blyth, David Sumpton, Saverio Tardito
Summary: This study reveals that glutamine synthetase (GS) can produce a methylated glutamine analog, N-5-methylglutamine, during the synthesis of glutamine. GS inhibition leads to decreased levels of N-5-methylglutamine in the liver and circulation in mice. The levels of N-5-methylglutamine in urine correlate with tumor burden and GS expression in a liver cancer model.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Fabio Hedayioglu, Emma J. Mead, Patrick B. F. O'Connor, Matas Skiotys, Owen J. Sansom, Giovanna R. Mallucci, Anne E. Willis, Pavel Baranov, C. Mark Smales, Tobias von der Haar
Summary: The study validates two experimental tools for assessing ribosome binding to mRNAs, highlighting the usefulness of polysome profile reconstructions in evaluating dataset quality.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biotechnology & Applied Microbiology
Lakshmeesha K. Nagappa, Wakana Sato, Farzana Alam, Kameshwari Chengan, Christopher M. Smales, Tobias von der Haar, Karen M. Polizzi, Katarzyna P. Adamala, Simon J. Moore
Summary: Cell-free gene expression systems are important tools in synthetic biology and industrial production. This study discovered a new, low-cost and widely available amino acid source that can replace commercial ones in these systems. The method is applicable to various cell-free gene expression systems.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2022)
Editorial Material
Biotechnology & Applied Microbiology
Anurag S. Rathore, C. Mark Smales, Andras Guttman
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Fuhui Chen, Sevim B. Gurler, David Novo, Cigdem Selli, Denis G. Alferez, Secil Eroglu, Kyriaki Pavlou, Jingwei Zhang, Andrew H. Sims, Neil E. Humphreys, Antony Adamson, Andrew Campbell, Owen J. Sansom, Cathy Tournier, Robert B. Clarke, Keith Brennan, Charles H. Streuli, Ahmet Ucar
Summary: Breast cancer stem cells (BCSC), responsible for treatment resistance, tumor recurrence, and metastasis, have been hindered by heterogeneity and lack of selective molecular targets. This study identifies RAC1B as a clinically relevant molecular target for BCSC-targeting therapies, highlighting its role in the maintenance of BCSC and their chemoresistance to doxorubicin.
Review
Biochemistry & Molecular Biology
Tobias von der Haar, Thomas E. Mulroney, Fabio Hedayioglu, Sathishkumar Kurusamy, Maria Rust, Kathryn S. Lilley, James E. Thaventhiran, Anne E. Willis, C. Mark Smales
Summary: In vitro transcribed, modified messenger RNAs (IVTmRNAs) have been widely used for COVID-19 vaccination and are being explored for other therapeutic applications. However, differences in genesis pathways, cell entry routes, and modifications affect how IVTmRNAs interact with cellular machinery and how efficiently they are translated. Understanding the similarities and differences in translation between IVTmRNAs and native mRNAs is crucial for improving their therapeutic efficacy.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Oncology
Natasha Malik, Jodie Hay, Hassan N. B. Almuhanna, Karen M. Dunn, Jamie Lees, Jennifer Cassels, Jiatian Li, Rinako Nakagawa, Owen J. Sansom, Alison M. Michie
Summary: This study reveals the essential role of mTORC1 in the initiation/maintenance of leukemia in a CLL model and identifies the inactivation of eEF2 activity as a novel therapeutic target for blocking CLL progression.
Review
Oncology
Simon T. Barry, Dmitry I. Gabrilovich, Owen J. Sansom, Andrew D. Campbell, Jennifer P. Morton
Summary: Myeloid cells in the tumour microenvironment have a significant impact on tumour progression, making them a key target for clinical therapies. However, large-scale clinical trials targeting these cells have had limited success. Understanding the specific functions and roles of different myeloid cell subpopulations within the tumour microenvironment could improve the design of successful clinical trials for myeloid-targeting therapies.
NATURE REVIEWS CANCER
(2023)
Article
Cell Biology
Yakinthi Chrisochoidou, Rajat Roy, Pooyeh Farahmand, Guadalupe Gonzalez, Jennifer Doig, Lukas Krasny, Ella F. Rimmer, Anne E. Willis, Marion MacFarlane, Paul H. Huang, Neil O. Carragher, Alison F. Munro, Daniel J. Murphy, Kirill Veselkov, Michael J. Seckl, Miriam F. Moffatt, William O. C. Cookson, Olivier E. Pardo
Summary: This study demonstrates that fibroblast activation in mesothelioma is a self-propagated process that triggers drug resistance in cancer cells. Several FDA-approved targeted therapies are found to be more potent than the standard treatment in co-culture models, with the SRC family kinase inhibitor Saracatinib showing significant improvement in overall survival. These findings lay the foundation for the development of novel therapeutic strategies targeting mesothelioma/fibroblast communication.
CELL DEATH & DISEASE
(2023)
Article
Oncology
Asif Ali, Nigel Balfour Jamieson, Ishaq N. Khan, David Chang, Elisa Giovannetti, Nicola Funel, Adam E. Frampton, Jennifer Morton, Owen Sansom, Thomas R. Jeffry Evans, Fraser Duthie, Colin J. McKay, Jas Samra, Anthony J. Gill, Andrew Biankin, Karin A. Oien
Summary: Despite the progress in genomic characterization, there is still a lack of an easy-to-perform and relatively inexpensive method to evaluate prognostic markers for pancreatic ductal adenocarcinoma (PDAC). This study established a validated method to investigate miR-21 as a potential prognostic biomarker for PDAC. The results showed that miR-21 expression was significantly associated with tumor size and lymph node metastasis, and high miR-21 staining was an independent predictor of survival in multiple cohorts of PDAC patients. Evaluation of miR-21 may provide new opportunities for stratification and management of PDAC patients.
AMERICAN JOURNAL OF CANCER RESEARCH
(2022)