Biochemical Society transactions最新文献

{"title":"Sensing of double-stranded RNA in human cells: molecular mechanisms and cellular consequences.","authors":"Julia Cieslicka, Karolina Pianka, Karolina Drazkowska, Pawel J Sikorski","doi":"10.1042/BST20250259","DOIUrl":"10.1042/BST20250259","url":null,"abstract":"<p><p>Double-stranded RNA (dsRNA) is a universal indicator of viral replication and dysregulated RNA metabolism. Detection of dsRNA triggers some of the most powerful innate immune responses in human cells. Although these molecules differ in origin and structure, viral dsRNAs share the defining geometric and electrostatic features of the A-form helix, enabling their sequence-independent recognition by multiple sensor systems. Cytosolic receptors, like retinoic acid-inducible gene I (RIG-I), melanoma differentiation associated gene 5 (MDA5), and protein kinase R (PKR), as well as the oligoadenylate synthase (OAS)/RNase L pathway, convert dsRNA binding into interferon induction, translational arrest, and widespread RNA decay, while endosomal Toll-like receptor 3 (TLR3) and the inflammasome sensor NLR family pyrin domain containing 1 (NLRP1) expand surveillance to internalised or structurally disruptive RNAs. Counterbalancing these pathways, the RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) marks endogenous dsRNA through A-to-I conversion, preventing inadvertent activation of innate immune response and maintaining self versus non-self discrimination. Although all of these sensors recognise the A-form helix, each extracts distinct structural and chemical information from dsRNA and converts it into a specific response: RIG-I detects short duplexes with 5'-triphosphorylated ends; MDA5 assembles cooperatively along long uninterrupted helices; PKR integrates duplex length with translational control; OAS proteins act as strict reporters of helix regularity; and TLR3 as well as NLRP1 respond to dsRNA in compartment- and context-dependent ways. Epitranscriptomic marks and chemical modifications-including 2'-O-methylation, N6-methyladenosine, pseudouridine, and ADAR1-mediated inosine-further refine sensing by modulating helical stability and end structure, establishing a biochemical 'self-code' that shapes RNA immunogenicity. Together, these pathways form an integrated network that distinguishes between viral and endogenous dsRNA and coordinates antiviral defence with immune tolerance.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 3","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The segregation of organelles and organellar genomes across eukaryotic biology.","authors":"Clirim Jetishi, Markus Gerber, Torsten Ochsenreiter","doi":"10.1042/BST20253120","DOIUrl":"10.1042/BST20253120","url":null,"abstract":"<p><p>Eukaryotic cells are characterized by the presence of organelles such as mitochondria and, in the case of plants and certain protists, plastids, both of which often contain their own genomes. Accurate distribution of replicated organelles and their genomes to daughter cells is crucial for cell survival and propagation across all eukaryotic organisms. Unlike nuclear DNA, which follows a well-characterized segregation process via the mitotic spindle, organelle genomes are inherited through more diverse and less-understood mechanisms. Ensuring proper organelle genome inheritance is essential for maintaining cellular energy production, metabolic functions, and overall viability. Because organelle and organelle genome segregation lack a universal mechanism, different organisms employ various strategies that include stochastic distribution and active cytoskeletal transport and membrane tethering to prevent the loss of essential genetic material while supporting organelle division and turnover. This review provides an overview of organelle and organellar DNA segregation mechanisms in diverse eukaryotic systems before focusing on the tripartite attachment complex as a specialized adaptation in kinetoplastid parasites.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 3","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methods for studying the effects of phosphorylation patterns in proteins.","authors":"Shachar Guy Bressler, Dana Grunhaus, Mattan Hurevich, Assaf Friedler","doi":"10.1042/BST20250137","DOIUrl":"10.1042/BST20250137","url":null,"abstract":"<p><p>Protein phosphorylation is one of the most common and versatile regulatory mechanisms in cells. Most human proteins are phosphorylated at multiple sites, giving rise to large numbers of possible phosphorylation patterns. Each phosphorylation pattern can lead to a different functional or pathological outcome. Yet, linking defined phosphorylation patterns to specific biological functions remains a major experimental challenge. In this review we describe the main strategies to study phosphorylation patterns at the protein and domain levels and highlight how they complement each other. We first discuss cellular approaches, including phosphomimetics, kinase-based assays, and genetic code expansion, which allow working in a native environment but have their significant drawbacks. We then describe in vitro methods, such as enzymatic phosphorylation and semi-synthetic phosphoproteins generated by ligation, which afford mechanistic insights but result in low yields and are difficult to scale for producing libraries. We focus on synthetic phosphopeptide libraries as tools that offer precise control over the number and position of phosphosites and are uniquely suited for systematic mapping of phosphorylation patterns. This comes at a price of not working at the protein level, but rather at the domain level. Peptide libraries are often used for preliminary identification of key phosphorylations, later studied in detail at the protein level. We conclude that ideally more than one method should be used and that these methods should not be viewed as competing but rather as complementary. A combined use of several of these approaches provides a practical toolbox for dissecting how phosphorylation patterns regulate protein behavior.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 3","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprogramming the inactive X chromosome: dynamics and insights from the germline.","authors":"Yolanda Moyano Rodriguez, Maud Borensztein","doi":"10.1042/BST20250549","DOIUrl":"10.1042/BST20250549","url":null,"abstract":"<p><p>Germline reprogramming is an essential process that resets the epigenome prior to gamete formation. Primordial germ cells (PGCs), the progenitors of oocytes and spermatozoa, undergo extensive epigenetic remodelling during development, including genome-wide DNA demethylation, histone modification remodelling, and large-scale reorganisation of 3D genome architecture. In female mammals, an additional layer of epigenetic regulation occurs during PGC reprogramming: the reactivation of the inactive X chromosome, namely, X-chromosome reactivation (XCR). Female PGC precursors carry an inactive X chromosome to ensure dosage compensation prior to reprogramming. While X-chromosome inactivation has been extensively studied for decades, XCR has only more recently emerged as a focus of investigation, and its functional importance for germline development and reproduction remains unclear. XCR takes place along PGC differentiation, from early emergence to meiosis, and involves loss of the long non-coding RNA XIST/Xist coating, DNA demethylation at X-linked promoters, and re-expression of X-linked genes from the inactivated X. Sequential molecular events occurring during XCR have been characterised using both in vivo and in vitro approaches in a broad range of mammals from rodents to humans. In recent years, the emergence of low-input and single-cell omics technologies has substantially advanced our understanding of the inactive X-chromosome reactivation in the germline. In this review, we synthetise recent insights into XCR dynamics in mouse, human, and non-human primate PGCs. We discuss the remaining knowledge gaps and the future perspectives in the field of XCR and germline epigenetic reprogramming.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 3","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human iPSCs: atrial versus ventricular cardiomyocytes and their functional and pharmacological differences.","authors":"Steven David Broadbent, Jamie Ronald Bhagwan, Tosin Olusoga, Ashley Barnes","doi":"10.1042/BST20253028","DOIUrl":"10.1042/BST20253028","url":null,"abstract":"<p><p>The continuing development and characterisation of human-induced pluripotent stem cell (hiPSC)-derived cell-types has opened up a virtually endless source of human, physiologically relevant cells, available at scale, for scientific research. The technology's maturation and refinement have allowed additional cell-types and sub-types to become available. The first step in adopting these novel cell-types is to properly characterise these cells and compare how they perform against the longer-established cell-types. Parallel to the progress in iPSC-derived cells has been the great strides in the platforms developed to assess and analyse the characteristics and functions of cells. These improved platforms have greatly increased the range, throughput and quality of the functional data that can be obtained from cell-types, including iPSC-derived cells. Research into cardiomyocytes in particular has been greatly enhanced by these platforms as cardiomyocytes not only have the expected cellular markers, proteomics and transcriptomics but are also electrically active and capable of contracting, opening a wide vista of potential assays. If human iPSC-derived cardiomyocytes are to confidently replace and supplement the existing animal and cellular models of the heart, it has to be demonstrated that they correctly replicate (or even improve) upon the functions and pharmacology of the existing heart models used on these new and improved platforms. Therefore, this review compares the functional and pharmacological differences seen between Axol's human iPSC-derived atrial and ventricular cardiomyocyte cells on a range of established and newer platforms demonstrating the advantages of using chamber-specific human iPSC-derived cardiomyocytes and discussing how their use could supplement these emerging techniques.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 2","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poxviral Bcl-2 proteins: multifunctional manipulators of the host cell.","authors":"Summer Smyth, Jianing Dong, Grace Melvie, Robert J Ingham","doi":"10.1042/BST20250100","DOIUrl":"10.1042/BST20250100","url":null,"abstract":"<p><p>Poxviruses are double-stranded DNA viruses that infect a wide range of animals. Their large genomes encode for over 200 proteins and many of these help establish infection by inhibiting cell death or interfering with host antiviral signalling pathways. This includes the poxviral B cell lymphoma-2 (Bcl-2) proteins, which are found in most of the Chordopoxvirinae (vertebrate-infecting poxviruses), with individual viruses possessing multiple Bcl-2 proteins. These proteins are so named for the fact that they adopt an alpha helical bundle with structural similarity to cellular anti-apoptotic Bcl-2 proteins, despite lacking obvious primary amino acid sequence identity with these proteins. Not surprisingly, initial studies found that some poxviral Bcl-2 proteins inhibit apoptosis; however, it was soon clear that these proteins have additional functions. This brief review highlights some of these other activities that have either been more recently identified or for which additional mechanistic insight has been acquired. This includes the role of poxviral Bcl-2 proteins in modulating nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein (NLRP) inflammasome activation and inhibiting antiviral signalling regulated by the interferon regulatory factor 3 and 7 (IRF3/7) transcription factors. Finally, we discuss how poxviral Bcl-2 proteins interfere with cellular antiviral TRIM family E3 ubiquitin-ligases to promote virus replication.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 2","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging liquid biopsy tools to analyse cancer biomarkers: electrochemical sensors and extracellular vesicle analysis.","authors":"Anitha Devadoss, Michael R Furness, Nathan J W Wu, Olga Oikonomidou, Maïwenn Kersaudy-Kerhoas, Nick R Leslie","doi":"10.1042/BST20253109","DOIUrl":"10.1042/BST20253109","url":null,"abstract":"<p><p>Better biomarker analysis technologies can provide improvements in the detection, characterisation and monitoring of cancer and less invasive sampling of blood and other body fluids can improve acceptability and affordability. Here, we discuss these technologies with a specific focus on recent advances in electrochemical sensors, specifically for the analysis of extracellular vesicles (EVs). Widely used biomarker tests with relatively high sensitivity (e.g. ELISAs) are limited by their cost, storage requirements and shelf-life, and ease of use away from centralised facilities. Moreover, their limits of detection (most commonly in the nanomolar to picomolar, with new technologies pushing into the femtomolar range) remain challenged by low abundance biomarkers. Here, we discuss how electrochemical sensor platforms, although often requiring more effort to adapt for new analytes, can provide high sensitivity and direct quantitation at low cost. These platforms are also often simpler to use away from testing facilities. Additionally, we explore how EVs, by protecting nucleic acid and protein cargos from degradation, may facilitate the collective enrichment from blood samples of multiple tumour-derived biomarkers. Continued progress in analysis technologies, alongside a deeper understanding of biomarker biology and clinical value, holds the potential to improve outcomes for the increasing numbers of individuals diagnosed with cancer.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 2","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA translocation by the CMG helicase: the helical inchworm model.","authors":"Sahil Batra, Benjamin Allwein, Y Lucia Wang, Richard K Hite, Dirk Remus","doi":"10.1042/BST20250145","DOIUrl":"10.1042/BST20250145","url":null,"abstract":"<p><p>In all cells, hexameric helicases drive the unwinding of parental chromosomal DNA at replication forks to provide the single-stranded DNA templates required by replicative DNA polymerases. DNA unwinding proceeds via a steric exclusion mechanism in which the helicase encircles and translocates along one DNA strand while sterically excluding the opposite strand from its central channel. The details of how hexameric helicases translocate on single-stranded DNA remain incompletely understood and likely vary among species, as structural and mechanistic features-such as motor domain architecture and translocation polarity-shape helicase function. Recent high-resolution cryo-EM structures of the eukaryotic CMG (Cdc45-MCM-GINS) helicase, including complexes stalled at leading-strand G-quadruplexes, reveal two predominant DNA-bound conformations: planar and spiral. These structures show that different subsets of MCM subunits alternately engage the leading-strand template, defining intermediates of a nonrotary, hand-over-hand translocation mechanism. This mode of translocation differs from the sequential rotary hand-over-hand mechanism proposed for bacterial hexameric helicases, instead resembling that of other ring-shaped ATPase motors and can be described as a variant of the helical inchworm model. The evolution of this mechanism may reflect CMG's specialized role as a replisome organizer, enabling it to coordinate accessory factors and optimize replication fork progression. Together, these findings highlight the mechanistic diversity and evolutionary adaptability of hexameric helicases.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 2","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Designing de novo TIM barrels: insights into stabilization, diversification, and functionalization strategies.","authors":"Julian Beck, Sergio Romero-Romero","doi":"10.1042/BST20253060","DOIUrl":"10.1042/BST20253060","url":null,"abstract":"<p><p>The triosephosphate isomerase (TIM)-barrel fold is one of the most versatile and ubiquitous protein folds in nature, hosting a wide variety of catalytic activities and functions while serving as a model system in protein biochemistry and engineering. This review explores its role as a key fold model in protein design, particularly in addressing challenges in stabilization and functionalization. We discuss historical and recent advances in de novo TIM barrel design from the landmark creation of sTIM11 to the development of the diversified variants, with a special focus on deepening our understanding of the determinants that modulate the sequence-structure-function relationships of this architecture. Also, we examine why the diversification of de novo TIM barrels toward functional diversification remains an open problem, given the absence of natural-like active site features. Current approaches have focused on incorporating structural extensions, modifying loops, and using cutting-edge AI-based strategies to create scaffolds with tailored characteristics. Despite significant advances, achieving enzymatically active de novo TIM barrels has been proven difficult, with only recent breakthroughs demonstrating functional activity. We discuss the limitations of stepwise design approaches and support integrated strategies that simultaneously optimize scaffold structure and active site shape, using both physics-based and AI-driven methods. By combining computational and experimental insights, we highlight the TIM barrel as a powerful template for custom enzyme design and as a model system to explore the intersection of protein biochemistry, biophysics, and design.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 2","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146155848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The application of single-molecule optical tweezers to study disease-related structural dynamics in RNA.","authors":"Tycho Marinus, Toshana Foster, Katarzyna Tych","doi":"10.1042/BST20231232_COR","DOIUrl":"10.1042/BST20231232_COR","url":null,"abstract":"","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 2","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}