Biochemical Society Transactions[JOURNAL]
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200 papers
Ins and outs of IRES elements: function and significance.
Martínez-Salas E
Biochem Soc Trans · 2025 Oct · PMID 41151051 · Full text
RNA and proteins are key components of all organisms. Internal ribosome entry site (IRES) elements are a diverse type of RNA regulatory structural elements that mediate end-independent, internal translation initiation in...
RNA and proteins are key components of all organisms. Internal ribosome entry site (IRES) elements are a diverse type of RNA regulatory structural elements that mediate end-independent, internal translation initiation in viral mRNAs and certain cellular mRNAs translated under stress conditions. Notably, viral IRES elements regulate translation initiation via a dynamic, modular RNA structure organization, which serves as the anchoring site for the ribosome guided by RNA-RNA and/or RNA-protein interactions. The implementation of advanced transcriptomics, proteomics, and computational methodologies has facilitated the identification of novel RNAs potentially translated using cap-independent mechanisms, harboring RNA structural elements with distinctive features. Here, we present a summary of the current understanding of IRES elements, focusing on the molecular functions and the RNA-binding proteins regulating IRES activity.
Are you having a LaPh? Diverse roles of Labile Phosphorylation in mammalian cells.
Clarke CJ, Eyers CE
Biochem Soc Trans · 2025 Oct · PMID 41124372 · Full text
Phosphorylation plays a central role in regulating signal transduction across all kingdoms of life, allowing organisms to sense and respond to their environment. In mammals, the signalling research field is dominated by...
Phosphorylation plays a central role in regulating signal transduction across all kingdoms of life, allowing organisms to sense and respond to their environment. In mammals, the signalling research field is dominated by the functions of pSer, pThr and pTyr, due to both historical and technological factors. Mostly ignored are the labile phosphosites (LaPhs), made up of six other phosphorylatable amino acids: His, Lys, Arg, Asp, Glu and Cys. This group is characterised by an acid and/or heat-labile phosphate linkage, forming a distinct group from the highly stable phosphomonoesters of pSer, pThr and pTyr. LaPhs have distinct thermal and pH stability profiles, which may contribute to, or even dictate, their functions. Here, we review the contribution of LaPhs to mammalian signalling networks, highlighting their currently defined diverse functions.
Deubiquitylases and nucleases in bacterial symbiont-induced cytoplasmic incompatibility.
Oladipupo SO, Hochstrasser M
Biochem Soc Trans · 2025 Oct · PMID 41124367 · Full text
In myriad arthropod species, maternally transmitted symbiotic bacteria spread through populations by manipulating host reproduction, most frequently by a mechanism called cytoplasmic incompatibility (CI). CI occurs when...
In myriad arthropod species, maternally transmitted symbiotic bacteria spread through populations by manipulating host reproduction, most frequently by a mechanism called cytoplasmic incompatibility (CI). CI occurs when bacterially infected males fertilize uninfected females, typically causing paternal chromatin condensation and segregation defects and usually embryonic arrest in the first zygotic cell cycle. Embryos survive if the female is similarly infected, which promotes bacterial spread. The endosymbiont best known for CI is Wolbachia, now widely used against mosquitoes that vector viral diseases such as dengue fever. Although CI is induced by Wolbachia resident in testes, mature sperm carry no bacteria, indicating they alter sperm in a way that, following fertilization, interferes with embryogenesis. CI-inducing factors (Cifs) are expressed from syntenic Wolbachia cifA-cifB genes. CifB is required in the male germline to induce CI, while CifA expression in the host female is sufficient to rescue viability. Importantly, CifA suppresses lethality through its binding to CifB. Different CifB proteins have distinct CI-relevant enzymatic functions, in particular, deubiquitylase and nuclease activities. Consistent with these genetic data, CifB is packaged into sperm during spermiogenesis. While sperm morphological disruption has been observed in fruit flies carrying cif transgenes, a causal role in CI is unclear. Also not understood is how maternally provisioned CifA rescues embryo viability. Exciting new findings with diverse symbiotic bacteria reveal cifA-cifB-like operons on extrachromosomal plasmids. These results suggest far wider deployment of Wolbachia-related CI factors than previously thought and multiple mechanisms for lateral cif gene transfer.
The many faces of the GID/CTLH E3 ligase complex.
Alpi AF, Chrustowicz J, Sherpa D … +1 more , Schulman BA
Biochem Soc Trans · 2025 Oct · PMID 41124358 · Full text
The GID/C-terminal to LisH (CTLH) E3 is an emerging family of evolutionarily conserved multiprotein E3 ligase complexes implicated in various biological processes including metabolic rewiring, stress-responsive regulatio...
The GID/C-terminal to LisH (CTLH) E3 is an emerging family of evolutionarily conserved multiprotein E3 ligase complexes implicated in various biological processes including metabolic rewiring, stress-responsive regulation, cellular differentiation, and immunity. Pioneering biochemical reconstitution, cryo-EM, and cell-based studies have illuminated many aspects of the compositional and structural dynamics of GID/CTLH E3 complexes. GID/CTLH E3 undergoes sophisticated regulation through incorporation of interchangeable substrate receptors and association with supramolecular assembly factors enabling higher-order complex formation. Furthermore, paralogous subunits vary and may modulate function across cell types. Additionally, an assortment of regulatory factors fine-tune substrate selection, underscoring the adaptability of this E3 ligase system. Here, we review these distinct ubiquitin ligase features, examine the mechanistic implications of GID/CTLH E3 regulation and the exquisite targeting of oligomeric substrates, and discuss potential for therapeutic application in targeted protein degradation.
Regulation of neutrophil function by the extracellular matrix.
Calo CJ, Radke M, Patil T … +1 more , Hind LE
Biochem Soc Trans · 2025 Oct · PMID 41104438 · Full text
Neutrophils play a critical role in maintaining healthy tissue by acting as the first cellular responders to inflammatory challenges. Unfortunately, when this response is dysregulated, defects in neutrophil function can...
Neutrophils play a critical role in maintaining healthy tissue by acting as the first cellular responders to inflammatory challenges. Unfortunately, when this response is dysregulated, defects in neutrophil function can contribute to the pathogenesis of several diseases and conditions, including cancer, fibrosis, and aberrant wound healing. Understanding the factors that regulate the neutrophil response is critical for improving disease outcomes. It is becoming increasingly appreciated that the extracellular matrix (ECM) serves as a significant regulator of the neutrophil response. The ECM is a complex network of fibrous proteins and proteoglycans that provides both physical and biochemical cues that can modulate cell behavior. Importantly, the composition, structure, and mechanics of the ECM often undergo significant changes in disease. Studies have shown that matrix stiffness and composition can alter neutrophil behavior, but our understanding of how the various structural and mechanical properties of the ECM govern the neutrophil response remains incomplete. In part, this is due to the challenges involved in isolating distinct properties of the matrix to determine their individual roles in regulating the neutrophil response. In this review, we summarize the recent efforts that have been made to better understand how ECM properties affect the neutrophil inflammatory response and offer suggestions for future directions for the field.
FASTK post-transcriptional regulators - a 'FAST-tracK' in mitochondrial gene expression.
Van Riper J, Corsaro BJ, Pillon MC
Biochem Soc Trans · 2025 Oct · PMID 41099336 · Full text
Fas-activated serine/threonine kinase (FASTK) proteins comprise one of the largest families of mitochondrial post-transcriptional regulators. Members are classified based on their conserved C-terminus, which shows homolo...
Fas-activated serine/threonine kinase (FASTK) proteins comprise one of the largest families of mitochondrial post-transcriptional regulators. Members are classified based on their conserved C-terminus, which shows homology with the PD-(D/E)XK superfamily of endoribonucleases. However, it is still uncertain which of these FASTK members are catalytic. The six human FASTK homologs rely on their RNA-binding activity to regulate distinct stages of mitochondrial gene expression, including early processing of nascent RNA, 3'-end messenger RNA (mRNA) maturation, ribosomal RNA (rRNA) modification, mRNA stability, and translation. Genetic and genomic studies have highlighted the crucial role of FASTK proteins in balancing the mitochondrial transcriptome and controlling oxidative phosphorylation. However, until recently, the molecular mechanisms governing their RNA metabolic activities have remained elusive. New biochemical and structural advances have provided molecular insights into the architecture and regulation of FASTK proteins. Here, we summarize the current understanding of the FASTK family's specialized roles in gene regulation, with an emphasis on mitochondrial mRNA metabolism by the proteins FASTK, FASTK domain-containing protein 4 (FASTKD4), and FASTKD5. Additionally, we leverage recent experimental structures and artificial intelligence-based prediction models to explore the molecular organization of FASTK proteins and highlight the family's signature C-terminus, a region essential for their RNA-binding activity.
Transcriptional condensates and the nuclear pore complex regulate gene expression and 3D genome architecture in response to stress.
Mohajan S, Gross DS
Biochem Soc Trans · 2025 Oct · PMID 41099333 · Full text
Cells respond to thermal, chemical, and oxidative stress by activating an evolutionarily conserved adaptive mechanism known as the heat shock response (HSR) that maintains protein homeostasis and ensures cell survival. C...
Cells respond to thermal, chemical, and oxidative stress by activating an evolutionarily conserved adaptive mechanism known as the heat shock response (HSR) that maintains protein homeostasis and ensures cell survival. Central to the HSR is Heat Shock Factor 1 (HSF1), a highly conserved master transcription factor that up-regulates genes encoding molecular chaperones and other homeostasis factors in response to proteotoxic stress. In both yeast and mammals, the HSR is accompanied by the inducible formation of phase-separated condensates that concentrate components of the transcriptional machinery into discrete intranuclear foci. The assembly of these condensates may be driven by a combination of liquid-liquid phase separation and low-valency Interactions with spatially Clustered Binding Sites (ICBS). In budding yeast, these condensates - which contain HSF1, Mediator, and RNA polymerase II - drive concerted intraand interchromosomal interactions between HSF1 target genes, creating extensive DNA loops between regulatory and transcribed sequences. In this and other ways, yeast HSR genes resemble mammalian super-enhancers. Emerging evidence suggests that the nuclear pore complex (NPC) - a macromolecular assembly at the nuclear periphery that regulates protein and RNA transport across the nuclear membrane - serves as a scaffold for the formation of transcriptional condensates and maintains chromatin architecture. In yeast, nuclear basket proteins - which dynamically exchange between the NPC and nucleoplasm - contribute to the heat shock-induced intergenic clustering of HSF1 target loci, whereas essential NPC scaffold-associated proteins do not. Such gene clustering is accompanied by the formation of multiplexed HSR mRNAs that could potentially co-ordinate both mRNA export and translation. Here we review evidence that links genome architecture, transcriptional condensates, the NPC, and nuclear basket proteins and discuss potential implications for the treatment of disease.
Correction: Anticancer drug development against ribosome synthesis and the nucleolus.
Loiacono A, Huang S
Biochem Soc Trans · 2025 Oct · PMID 41082718 · Full text
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Critical roles of plasma membrane dynamics and heterogeneity at the early stage of antigen-stimulated FcεRI signaling in mast cells.
Medda D, Bag N
Biochem Soc Trans · 2025 Oct · PMID 41065380 · Full text
Stimulated transmembrane (TM) signaling mediated by plasma membrane localized receptors is central to numerous cellular processes, and their dysregulation leads to pathological conditions. Antigen (Ag) stimulated cluster...
Stimulated transmembrane (TM) signaling mediated by plasma membrane localized receptors is central to numerous cellular processes, and their dysregulation leads to pathological conditions. Antigen (Ag) stimulated clustering of high-affinity immunoglobulin E (IgE) receptor FcεRI and its functional coupling of selective signaling components such as kinases, but not phosphatases, in the early stage of mast cell signaling represents the general paradigm of TM signaling mediated by membrane receptors lacking kinase module. It has been long thought that plasma membrane organizational features, especially ordered regions and cortical cytoskeletons network, play crucial roles in efficient spatial sorting of the signaling components. In this review, we highlight the observations made by advanced imaging and spectroscopy techniques at high spatial and temporal resolution that essentially establish novel principles of plasma membrane 'adaptivity' in regulating the initial steps of stimulated mast cell signaling involving Ag cross-linked IgE-FcεRI receptor.
PROTACs in cancer immunotherapy: a minireview.
J E K, E S CA, E T C … +2 more , J S G, F M F
Biochem Soc Trans · 2025 Oct · PMID 41032705 · Full text
The discovery of immune checkpoint blockade as a therapeutic strategy to induce immunogenic cancer cell elimination has shown great success in the treatment of various cancers. However, limited response rates highlight t...
The discovery of immune checkpoint blockade as a therapeutic strategy to induce immunogenic cancer cell elimination has shown great success in the treatment of various cancers. However, limited response rates highlight the need for further development in this field. Promising new preclinical developments include the discoveries of proteolysis-targeting chimeras (PROTACs) to interfere with tumor immune escape signaling. Pharmacological induction of targeted protein degradation by these chimeras has shown advantages in inhibiting non-enzymatic protein functions and difficult to target protein-protein interactions. Furthermore, the induced degradation was shown to promote changes in the major histocompatibility complex I ligandome, which can be leveraged for an immune stimulus, increasing the cancer immune response. In this minireview, we highlight the research efforts ongoing towards employing PROTACs in immunotherapy for cancer treatment. Specifically, we outline how the unique mechanism of action can be leveraged to enhance the immune response or inhibit immune suppression.
Move over endosymbionts, peroxisomes pass electrons too.
Walker BJ, Smith EN, Sweetlove LJ
Biochem Soc Trans · 2025 Oct · PMID 41026000 · Full text
The importance of the peroxisome as a site of oxidative metabolism in plants is well recognised, but the consequences of peroxisomal biochemistry for the broader metabolic network of plant cells are somewhat overlooked....
The importance of the peroxisome as a site of oxidative metabolism in plants is well recognised, but the consequences of peroxisomal biochemistry for the broader metabolic network of plant cells are somewhat overlooked. In this review, we place a spotlight on the peroxisome as a redox-active organelle which mediates substantial flows of electrons. These electron flows not only have consequences within the peroxisome, but they also flow to and from the cytosol and at least two other major redox-active organelles, chloroplasts and mitochondria, with broad implications for metabolism and redox balance of electron carriers such as NADPH and NADH. We will outline the nature of these peroxisome-mediated electron flows and discuss the new appreciation of their quantitative significance derived from metabolic network flux analysis. We emphasise that the flows of reducing equivalents into and out of the peroxisome can be substantial - in some tissues equivalent to that to and from mitochondria. We also highlight key areas of uncertainty around specific redox reactions in the peroxisome and open questions about how redox state is balanced. Finally, we also consider the implications of peroxisomal electron flows in the context of re-engineering key metabolic processes such as photorespiration and lipid accumulation.
New molecular targets in acute leukemias: cytoskeletal regulatory proteins.
Machado-Neto JA, Vicari HP, Lipreri da Silva JC … +1 more , Lima K
Biochem Soc Trans · 2025 Oct · PMID 40982350 · Full text
Acute leukemias are hematological malignancies characterized by the uncontrolled proliferation of immature bone marrow cells, disrupting normal hematopoiesis. These diseases, classified into acute lymphoblastic leukemia...
Acute leukemias are hematological malignancies characterized by the uncontrolled proliferation of immature bone marrow cells, disrupting normal hematopoiesis. These diseases, classified into acute lymphoblastic leukemia and acute myeloid leukemia (AML), often result from acquired genetic alterations that drive deregulated cell growth and inhibit differentiation. The cytoskeleton has emerged as a promising therapeutic target due to its pivotal role in cellular processes such as adhesion, motility, and division. Among its components, stathmin 1 (STMN1) and ezrin (EZR) stand out for their significant involvement in the pathogenesis and progression of acute leukemias. STMN1, a regulator of microtubule dynamics, is associated with chromosomal instability and leukemic cell proliferation, and is frequently overexpressed in these malignancies. Anti-microtubule agents, such as paclitaxel, eribulin, and cyclopenta[b]indole derivatives have demonstrated the ability to inhibit STMN1 by inducing its phosphorylation at regulatory sites, thereby impairing cell viability and promoting apoptosis. EZR, a membrane-actin linker protein, plays a critical role in cell signaling and tumor survival. Its overexpression has been correlated with poor prognosis in AML. Pharmacological inhibitors like NSC305787 have shown efficacy in reducing cell viability, modulating key pathways such as PI3K (phosphatidylinositol-3-kinase)/AKT (AKT serine-threonine protein)/mTOR (mammalian target of rapamycin), and enhancing the activity of standard chemotherapeutics, thereby supporting their potential use in combination therapies. This review aims to explore the roles of STMN1 and EZR in the pathogenesis of acute leukemias, assessing their potential as therapeutic targets. The goal is to synthesize recent evidence to guide the development of more effective inhibitors, focusing on overcoming therapeutic resistance and tailoring treatments to individual profiles.
Mechanisms underpinning natural variation in non-photochemical quenching kinetics.
Glowacka K
Biochem Soc Trans · 2025 Oct · PMID 40966385 · Full text
Plants use light as an energy source to reduce carbon dioxide into carbohydrates during photosynthesis. However, when the incident light exceeds the photosynthesis rate, the excess energy must be dispersed, or it can res...
Plants use light as an energy source to reduce carbon dioxide into carbohydrates during photosynthesis. However, when the incident light exceeds the photosynthesis rate, the excess energy must be dispersed, or it can result in the unregulated formation of harmful reactive oxygen species, especially in plants exposed to very high light or abiotic stress conditions that compromise photosynthetic efficiency. The excess energy is typically dispersed harmlessly as heat, which can be measured as non-photochemical quenching (NPQ) of chlorophyll fluorescence. NPQ kinetics vary within plant populations, and understanding the basis of this variation will contribute to improving resiliency to abiotic stresses, including high light, in crops. Here it is reviewed how three key NPQ genes, Photosystem II subunit S (PsbS), Violaxanthin de-epoxidase (VDE), and Zeaxanthin epoxidase (ZEP), contribute to natural variation in NPQ kinetics. PsbS expression level is an important determinant of NPQ variation, whereas VDE and ZEP contribute to NPQ variation via post-translational regulation related to natural variation in many genes affecting these enzymes' activity. Post-translational mechanisms that influence NPQ, including redox regulation via thioredoxins and regulation of ascorbate availability, thylakoid lumen pH, and violaxanthin accessibility are discussed. There are also addressed NPQ regulatory mechanisms beyond PsbS, ZEP, and VDE, including natural regulation of light accessibility, modulation of light harvesting, and feedback from the steps following light harvesting. Finally, how this knowledge can be harnessed to engineer more resilient crops is briefly summarized.
The regulatory mechanisms controlling meiotic cross-over patterning in plants.
Xu W, Lian Q, Li M … +2 more , Copenhaver GP, Wang Y
Biochem Soc Trans · 2025 Oct · PMID 40944364 · Full text
Most sexually reproducing eukaryotes use a specialized cell division called meiosis to halve the complement of chromosomes in their gametes. During meiotic prophase I, homologous chromosomes (homologs) recombine by recip...
Most sexually reproducing eukaryotes use a specialized cell division called meiosis to halve the complement of chromosomes in their gametes. During meiotic prophase I, homologous chromosomes (homologs) recombine by reciprocally exchanging DNA to form cross-overs (COs) that are required for accurate chromosome segregation. COs also reshuffle parental genomes to create genetic diversity among progeny. Molecular genetic studies have identified hundreds of genes involved in meiotic recombination, which have been well summarized in several reviews. Here, we highlight recent advances in understanding endogenous mechanisms that regulate the frequency and distribution of meiotic COs, also called CO patterning. Specifically, we focus on genome-wide regulation, epigenetic control, transcription regulation, and post-transcription processes. Additionally, we highlight open questions that still need further investigation in this field.
The impact of ribosome association on lncRNA stability: a new layer of post-transcriptional control?
Pienaar CK, Towler BP, Newbury SF
Biochem Soc Trans · 2025 Oct · PMID 40944360 · Full text
Long non-coding RNAs (lncRNAs) play crucial roles in cellular processes; however, the mechanisms controlling their stability are not well understood. Since the appropriate levels of lncRNAs in cells are required to carry...
Long non-coding RNAs (lncRNAs) play crucial roles in cellular processes; however, the mechanisms controlling their stability are not well understood. Since the appropriate levels of lncRNAs in cells are required to carry out their functions, it is critical that their degradation is tightly controlled. Extensive research has shown that translation and degradation of messenger RNAs (mRNAs) are intricately linked, with repression of translation usually leading to degradation of the RNA. Recently, evidence has emerged to suggest that translation may also affect lncRNA stability. Ribosome engagement may stabilise lncRNAs by protecting them from nucleases or by promoting their degradation via ribosome-associated decay pathways such as nonsense-mediated decay. In this review, we first highlight specific human diseases that result from misregulation of lncRNA stability. We then explore the mechanisms underlying ribosome association and lncRNA stability, drawing comparisons with canonical mRNA mechanisms and highlighting emerging hypotheses that may be particularly relevant to lncRNAs. We also discuss how advanced techniques such as ribosome profiling can be applied to investigate whether lncRNAs are translated. Finally, we suggest future strategies to aid further understanding of lncRNA stability and its relationship with development and disease. Understanding the dynamic relationship between translation and lncRNA decay offers broad implications for RNA biology and provides new insights into the regulation of lncRNAs in both cellular and disease contexts.
Structural and evolutionary insights into understudied bacterial serine-threonine pseudokinase families.
O'Boyle B, Bhowmik DR, Eyers PA … +2 more , Byrne DP, Kannan N
Biochem Soc Trans · 2025 Oct · PMID 40944356 · Full text
Pseudokinases, once considered catalytically inactive remnants of evolution, have emerged as key regulators of numerous fundamental biological processes. While eukaryotic pseudokinases have attracted significant attentio...
Pseudokinases, once considered catalytically inactive remnants of evolution, have emerged as key regulators of numerous fundamental biological processes. While eukaryotic pseudokinases have attracted significant attention, bacterial pseudokinases remain largely unexplored experimentally. Recent advances in sequence analysis and structural modeling have identified and characterized multiple conserved bacterial pseudokinase families, each with distinct predicted catalytic impairments but unknown functions. This review delves into their classification, structural features, and evolutionary adaptation. We also highlight the significance of bacterial pseudokinases in host-microbe interactions and their emerging potential as therapeutic targets. By integrating bioinformatics with experimental approaches, future research is poised to uncover the biological functions of bacterial pseudokinases, providing new insights into microbial signaling mechanisms and revealing new strategies to interrogate bacterial cell signaling, including pseudokinase drivers of infection and antimicrobial drug resistance.
Mechanistic insights into MET exon 14 skipping mutations and their role in tumor progression.
Ghosh P, Pecora I, Park M
Biochem Soc Trans · 2025 Oct · PMID 40924941 · Full text
The MET receptor tyrosine kinase is a pivotal regulator of cellular survival, motility, and proliferation. Mutations leading to skipping of exon 14 (METΔex14) within the juxtamembrane domain of MET impair receptor degrad...
The MET receptor tyrosine kinase is a pivotal regulator of cellular survival, motility, and proliferation. Mutations leading to skipping of exon 14 (METΔex14) within the juxtamembrane domain of MET impair receptor degradation and prolong oncogenic signaling, contributing significantly to tumor progression across multiple cancer types. METΔex14 mutations are associated with aggressive clinical behavior, therapeutic resistance, and poor outcomes. Next-generation sequencing from both tissue and liquid biopsies has significantly improved the detection frequency of METΔex14 in lung and other cancers. However, clinical trials targeting METΔex14 have rendered partial responses and mixed outcomes due to the lack of a comprehensive mechanistic understanding of METΔex14 regulation and a diverse mutational landscape. This review synthesizes current knowledge on the mechanistic basis of METΔex14-driven oncogenesis, including alterations in receptor dynamics, downstream signaling perturbations, genomic alterations underlying this mutation, and mechanisms of acquired therapeutic resistance. We further discuss the clinical implications of these insights and highlight future research directions essential for optimizing targeted therapies.
Insights from deep mutational scanning in the context of an emerging pathogen.
Call MJ, Call ME, Wu X
Biochem Soc Trans · 2025 Oct · PMID 40905952 · Full text
Deep mutational scanning (DMS), a high-throughput method leveraging next-generation sequencing, has been crucial in mapping the functional landscapes of key severe acquired respiratory syndrome-coronavirus 2 (SARS-CoV-2)...
Deep mutational scanning (DMS), a high-throughput method leveraging next-generation sequencing, has been crucial in mapping the functional landscapes of key severe acquired respiratory syndrome-coronavirus 2 (SARS-CoV-2) proteins. By systematically assessing thousands of amino acid changes, DMS provides a framework to understand Angiotensin-converting enzyme 2 (ACE2) binding and immune evasion by the spike protein, mechanisms and drug escape potential of the main and papain-like viral proteases and has highlighted areas of concern in the nucleocapsid protein that may affect most currently available rapid antigen testing kits. Each application has required the design of bespoke assays in eukaryotic (yeast and mammalian) cell models, providing an exemplar for the application of this technique to future pandemics. This minireview examines how DMS has predicted key evolutionary changes in SARS-CoV-2 and affected our understanding of SARS-CoV-2 biology, specifically highlighting their relevance for therapeutics development.
Using modified mRNA for cardiomyocyte proliferation and cardiac genetic disease modelling and treatment.
Batho CAP, Hudson JE, Wilson CH
Biochem Soc Trans · 2025 Oct · PMID 40905915 · Full text
Heart failure (HF) is a leading cause of death worldwide and the associated mortality and socioeconomic burden is predicted to worsen. Current therapies for HF focus on managing the causes and symptoms; however, these cu...
Heart failure (HF) is a leading cause of death worldwide and the associated mortality and socioeconomic burden is predicted to worsen. Current therapies for HF focus on managing the causes and symptoms; however, these current treatment options are unable to reverse heart muscle degeneration, with heart transplantation the only cure. The ability to re-muscularise the heart represents a significant unmet clinical need. Although numerous biological pathways driving re-muscularisation have been identified, delivery of therapeutic factors is challenging. Modified mRNA (modRNA) is synthetic mRNA with greater gene packaging capacity, low immunogenic response and allows transient but robust protein expression. In this mini-review, we highlight the emerging discoveries surrounding the application of modRNA in the cardiovascular field. Specifically, we focus on different examples illustrating how modRNA delivery post-myocardial infarction can drive cardiomyocyte proliferation and achieve cardiac regeneration. In addition, we demonstrate how modRNA is being used for protein replacement and Cas delivery for both modelling and therapeutic studies focussed on genetic cardiac diseases. For these applications, in particular Cas delivery, the transient nature of modRNA overexpression is a beneficial property with reduced side effects compared with other modalities. Finally, we preview some of the roadblocks limiting the clinical translation of modRNA and avenues being explored to overcome these. In summary, the flexibility of modRNA combined with its improved safety profile provides a gene overexpression tool capable of integration into all steps of the preclinical and clinical therapeutic pipeline enabling the discovery of improved treatments for HF.
Recent insights into the implications of UGDH mutations for human developmental disease.
Harwood H, Zimmer BM, Utz AR … +2 more , Barycki JJ, Simpson MA
Biochem Soc Trans · 2025 Aug · PMID 40879729 · Full text
Congenital disorders of glycosylation are a significant underlying cause of developmental and epileptic encephalopathy (DEE). A subset of these DEE cases results from biallelic variants in the unique, essential gene enco...
Congenital disorders of glycosylation are a significant underlying cause of developmental and epileptic encephalopathy (DEE). A subset of these DEE cases results from biallelic variants in the unique, essential gene encoding UDP-glucose dehydrogenase (UGDH). The UGDH enzyme catalyzes two successive NAD+- dependent oxidation reactions to convert the C6 hydroxyl of UDP-glucose to a carboxylate, generating the UDP-glucuronate product. This product is required for three critical reactions that generate: (1) hyaluronan, (2) secreted and cell surface proteoglycans, and (3) glucuronide conjugates for cellular detoxification. UGDH polymorphisms are not frequently observed as they are largely deleterious. However, a number of UGDH variants have been reported and characterized as causative agents of congenital defects in cardiac valve and brain development, and most recently of dystroglycanopathy. The effects of these mutations, clinically and at the molecular level, are summarized and discussed in this review.
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