Nucleic Acids Research最新文献

{"title":"The ParB-CTP cycle activates phase separation in bacterial DNA segregation","authors":"Linda Delimi, Perrine Revoil, Hicham Sekkouri Alaoui, Jérôme Rech, Jean-Yves Bouet, Jean-Charles Walter","doi":"10.1093/nar/gkaf944","DOIUrl":"https://doi.org/10.1093/nar/gkaf944","url":null,"abstract":"Cell function relies on liquid-like membraneless organelles formed through phase transitions, yet the mechanisms ensuring their specificity and rapid assembly remain poorly understood. In bacterial chromosome segregation via the ParABS system, hundreds of ParB proteins are recruited around the centromere-like parS sequence, forming the partition complex. Recent studies have shown that ParB binds CTP and undergoes cycles of loading and unloading near parS; however, this accounts for the recruitment of only a small fraction of ParB molecules, leaving its role unclear. Separately, a lattice gas model with fixed interaction energy has been proposed to describe ParB phase separation, but it fails to explain key experimental observations, including the absence of droplets in ParB variants. We reconcile these two perspectives by proposing that the ParB-CTP cycle acts as a molecular switch that enhances ParB–ParB interactions, triggering phase transition from vapor to liquid-like condensates. Our hypothesis is supported by numerical simulations of droplet formation and experiments showing that ParB variants disrupting the CTP cycle fail to undergo phase separation. These findings establish a mechanistic framework for ParB-CTP-mediated phase transitions and may have broader implications for understanding the spatial control of intracellular condensate formation.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"28 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and evolutionary determinants of Argonaute function","authors":"Arndt Wallmann, Mathew Van de Pette","doi":"10.1093/nar/gkaf962","DOIUrl":"https://doi.org/10.1093/nar/gkaf962","url":null,"abstract":"Members of the Argonaute protein superfamily adopt functions ranging from host-defense to mediating elaborate and multicomponent post-transcriptional and epigenetic systems of control. Despite this diversity of biological roles, the Argonaute structural fold is highly conserved throughout all domains of life. This raises questions about how Argonautes evolved to adapt to this increasing complexity of function, while conserving features that are broadly shared across the phylogenetic tree. Integrating structural, sequence, phylogenetic data, and disease-related mutational data, we compiled a comprehensive study of the Argonaute evolutionary trajectory. By comparing Argonaute proteins across a diverse set of lineages and extensive evolutionary timescale, we identified universal and clade-specific sequence signatures and intra-protein contact networks that underlie the Argonaute structural fold, nucleic acid interface and protein–protein binding sites. We analyze how these features are affected by disease-related mutations and are fundamentally altered in the case of the Argonaute-like Med13 protein. With this work we gain better insights into how Argonaute function diversified in eAgos by tracing the emergence of conserved molecular features that are associated with new biological functions.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"118 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On metrics for subpopulation detection in single-cell and spatial omics data","authors":"Siyuan Luo, Pierre-Luc Germain, Ferdinand von Meyenn, Mark D Robinson","doi":"10.1093/nar/gkaf921","DOIUrl":"https://doi.org/10.1093/nar/gkaf921","url":null,"abstract":"Benchmarks are crucial to understanding the strengths and weaknesses of the growing number of tools for single-cell and spatial omics analysis. A key task is to distinguish subpopulations within complex tissues, where evaluation typically relies on external clustering validation metrics. Different metrics often lead to inconsistencies between rankings, highlighting the importance of understanding the behavior and biological implications of each metric. In this work, we provide a framework for systematically understanding and selecting validation metrics for single-cell data analysis, addressing tasks such as creating cell embeddings, constructing graphs, clustering, and spatial domain detection. Our discussion centers on the desirable properties of metrics, focusing on biological relevance and potential biases. Using this framework, we not only analyze existing metrics but also develop novel ones. Delving into domain detection in spatial omics data, we develop new external metrics tailored to spatially aware measurements. Additionally, a Bioconductor R package, poem, implements all the metrics discussed. While we focus on single-cell omics, much of the discussion is of broader relevance to other types of high-dimensional data.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"28 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MITE: the Minimum Information about a Tailoring Enzyme database for capturing specialized metabolite biosynthesis","authors":"Adriano Rutz, Daniel Probst, César Aguilar, Daniel Y Akiyama, Fabrizio Alberti, Hannah E Augustijn, Nicole E Avalon, Christine Beemelmanns, Hellen Bertoletti Barbieri, Friederike Biermann, Alan J Bridge, Esteban Charria Girón, Russell Cox, Max Crüsemann, Paul M D’Agostino, Marc Feuermann, Jennifer Gerke, Karina Gutiérrez García, Jonathan E Holme, Ji-Yeon Hwang, Riccardo Iacovelli, Júlio César Jeronimo Barbosa, Navneet Kaur, Martin Klapper, Anna M Köhler, Aleksandra Korenskaia, Noel Kubach, Byung T Lee, Catarina Loureiro, Shrikant Mantri, Simran Narula, David Meijer, Jorge C Navarro-Muñoz, Giang-Son Nguyen, Sunaina Paliyal, Mohit Panghal, Latika Rao, Simon Sieber, Nika Sokolova, Sven T Sowa, Judit Szenei, Barbara R Terlouw, Heiner G Weddeling, Jingwei Yu, Nadine Ziemert, Tilmann Weber, Kai Blin, Justin J J van der Hooft, Marnix H Medema, Mitja M Zdouc","doi":"10.1093/nar/gkaf969","DOIUrl":"https://doi.org/10.1093/nar/gkaf969","url":null,"abstract":"Secondary or specialized metabolites show extraordinary structural diversity and potent biological activities relevant for clinical and industrial applications. The biosynthesis of these metabolites usually starts with the assembly of a core ‘scaffold’, which is subsequently modified by tailoring enzymes to define the molecule’s final structure and, in turn, its biological activity profile. Knowledge about reaction and substrate specificity of tailoring enzymes is essential for understanding and computationally predicting metabolite biosynthesis, but this information is usually scattered in the literature. Here, we present MITE, the Minimum Information about a Tailoring Enzyme database. MITE employs a comprehensive set of parameters to annotate tailoring enzymes, defining substrate and reaction specificity by the expressive reaction SMARTS (Simplified Molecular Input Line Entry System Arbitrary Target Specification) chemical pattern language. Both human and machine readable, MITE can be used as a knowledge base, for in silico biosynthesis, or to train machine-learning applications, and tightly integrates with existing resources. Designed as a community-driven and open resource, MITE employs a rolling release model of data curation and expert review. MITE is freely accessible at https://mite.bioinformatics.nl/.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"15 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coordinated control of genome–nuclear lamina interactions by topoisomerase 2B and lamin B receptor","authors":"Tom van Schaik, Mikhail Magnitov, Marcel de Haas, Jeremie Breda, Elzo de Wit, Anna G Manjon, René H Medema, Henrike Johanna Gothe, Vassilis Roukos, Adam J Buckle, Catherine Naughton, Nick Gilbert, Bas van Steensel, Stefano G Manzo","doi":"10.1093/nar/gkaf964","DOIUrl":"https://doi.org/10.1093/nar/gkaf964","url":null,"abstract":"Lamina-associated domains (LADs) are megabase-sized genomic regions anchored to the nuclear lamina (NL). Factors controlling the interactions of the genome with the NL have largely remained elusive. Here, we identified DNA topoisomerase 2 beta (TOP2B) as a regulator of these interactions. TOP2B binds predominantly to inter-LAD (iLAD) chromatin and its depletion results in a partial loss of genomic partitioning between LADs and iLADs, suggesting that this enzyme might protect specific iLADs from interacting with the NL. TOP2B depletion affects LAD interactions with lamin B receptor (LBR) more than with lamins. LBR depletion phenocopies the effects of TOP2B depletion, despite the different positioning of the two proteins in the genome. This suggests a complementary mechanism for organizing the genome at the NL. Indeed, co-depletion of TOP2B and LBR causes partial LAD/iLAD inversion, reflecting changes typical of oncogene-induced senescence. We propose that a coordinated axis controlled by TOP2B in iLADs and LBR in LADs maintains the partitioning of the genome between the NL and the nuclear interior.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"94 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare Cancer Explorer 1.0 (RaCE 1.0): a dedicated database and analytical platform focused on rare cancers.","authors":"Yihao Chen,Le Zhang,Chuanfan Zhong,Songbo Li,Ruidong Li,Zhenyu Jia,Peisheng Huang,Shuo Wang,Zitao He,Huawei Lin,Xiaowen Lin,Kai Chen,Zhuoya Huang,Shanshan Mo,Zhouda Cai,Junhong Deng,Weide Zhong,Jiahong Chen,Jianming Lu","doi":"10.1093/nar/gkaf911","DOIUrl":"https://doi.org/10.1093/nar/gkaf911","url":null,"abstract":"Rare cancers face major research challenges due to limited sample sizes and data scarcity. Existing pan-cancer databases mainly focus on common cancer types, while rare cancers often lack sufficient attention and systematic data collection. In addition, their high heterogeneity and the scarcity of studies on genomic features, immune environments, and drug responses lead to significant gaps in current databases and analytical tools. To address these limitations, we developed the Rare Cancer Explorer (RaCE), a dedicated database for integrated curation, analysis, and visualization of rare cancers. RaCE consolidates 5451 samples spanning 13 rare solid tumor types from 69 independent datasets, offering researchers a one-stop data analysis toolkit. The database provides one integrated dataset meta-analysis module and eight dedicated rare cancer functional analysis modules, including transcriptomics, immune infiltration, and immunotherapy response prediction, with a specialized focus on modeling gene effects and drug sensitivity in rare cancer cell lines. RaCE distinguishes itself through robust interactive functionalities, enabling users to seamlessly explore multi-layered insights from gene functions to therapeutic targets, thereby accelerating precision medicine and translational research for rare cancers. Compared to existing databases, RaCE demonstrates unique advantages in supporting rare cancer research through comprehensive data integration. The database is freely accessible at https://biospace.shinyapps.io/race/ or https://hiplot.com.cn/race/.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"30 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the origin, evolution, and maintenance of RNA editing.","authors":"Yuange Duan,Qi Cao,Qiuhua Xie,Ling Ma,Wanzhi Cai,Hu Li","doi":"10.1093/nar/gkaf947","DOIUrl":"https://doi.org/10.1093/nar/gkaf947","url":null,"abstract":"A newly published review by Bendich and Rogers (The biological and evolutionary consequences of competition between DNA sequences that benefit the cell and DNA sequences that benefit themselves. Nucleic Acids Research2025;53:gkaf589.) discusses the origin of RNA editing as a defense against mobile genetic elements (MGEs) and points out that many recent reviews, including ours, failed to recognize this fundamental issue. In this article, we expand on this perspective by examining the mechanistic and theoretical gaps regarding whether RNA editing suppresses or tolerates TE proliferation. We highlight the relevance of constructive neutral evolution (CNE) theory, suggesting that regardless of whether the editing machinery has arisen via CNE, specific editing sites do exhibit CNE signals. Additionally, we explore why certain A-to-I recoding sites are selectively maintained without being replaced with genomic G, reinforcing their indispensable regulatory role. Taken together, while acknowledging the plausibility of the MGE-related origin, we advocate for a broader view of RNA editing that includes multiple fascinating functions like proteome diversification and mutation correction.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"35 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opposing roles of two R-loop associated G-quadruplexes in tuning transcription activity.","authors":"Leya Yang,Chun-Ying Lee,Tapas Paul,Sua Myong","doi":"10.1093/nar/gkaf930","DOIUrl":"https://doi.org/10.1093/nar/gkaf930","url":null,"abstract":"Guanine (G)-rich sequences in nucleic acids can form non-canonical secondary structures such as R-loops and G-quadruplexes (G4) during transcription. The R-loop formed on the template strand promotes and stabilizes G4 in the non-template strand. However, the precise role of G4/R-loop-forming sequences on transcription remains poorly understood. In this study, we investigated the effect of different potential G4-forming sequences (PQSs) on G4/R-loop formation and transcription dynamics. We employed gel-based assays and single-molecule fluorescence resonance energy transfer (smFRET) to measure RNA synthesis and concomitant formation of G4 and R-loop during transcription by T7 RNA polymerase. We reveal two types of R-loop that form successively; an R-loop with an intramolecular DNA G4 (IG4) initially forms during transcription, followed by an R-loop with an intermolecular DNA:RNA hybrid G4 (HG4). We found that IG4 R-loops inhibit, whereas HG4 R-loops enhance transcription. We identified that an HG4/IG4 ratio highly correlates with transcriptional activity. PQS with short linkers favors IG4, reducing transcription, while PQS with long linkers that induce loosely folded PQS favor HG4, increasing transcription. Since IG4 formation precedes HG4, tightly folded PQS forms IG4 quickly and stably, slowing its conversion to HG4 and reducing transcriptional enhancement.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"99 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OncoDB 2.0: a comprehensive platform for integrated pan-cancer omics analysis.","authors":"Minsu Cho,Gongyu Tang,Charles S Rogers,Makayla Dove,Xinyi Liu,Yuanxiang Li,Xiaowei Wang","doi":"10.1093/nar/gkaf952","DOIUrl":"https://doi.org/10.1093/nar/gkaf952","url":null,"abstract":"OncoDB was initially developed to advance cancer research by integrating RNA expression profiles, DNA methylation patterns, clinical annotations, and oncoviral signatures derived from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression datasets. We now present OncoDB 2.0, an extensively expanded platform that offers a more comprehensive and integrated view of cancer omics. The updated version includes an atlas of somatic mutations discovered from combined DNA and RNA sequencing, enabling in-depth investigation of mutation patterns across tumor types and their association with clinical features. Furthermore, we have integrated proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and chromatin accessibility data from TCGA, offering new dimensions for oncogene regulation studies. OncoDB 2.0 also introduces advanced multi-omics analysis modules that facilitate the combined exploration of RNA expression, DNA methylation, and somatic mutations, allowing researchers to examine complex cross-omic relationships with greater depth and flexibility. Together, these enhancements make OncoDB 2.0 a robust and invaluable tool for the cancer research community. OncoDB 2.0 is freely available at https://oncodb.org.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"49 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatiotemporal dynamics and selectivity of mRNA translation during mouse pre-implantation development.","authors":"Hao Ming, Rajan Iyyappan, Kianoush Kakavand, Michal Dvoran, Andrej Susor, Zongliang Jiang","doi":"10.1093/nar/gkaf956","DOIUrl":"10.1093/nar/gkaf956","url":null,"abstract":"<p><p>Translational regulation plays a pivotal role during pre-implantation development. However, the mechanisms by which messenger RNAs (mRNAs) are selectively regulated over time, along with their dynamic utilization and fate during this period, remain largely unknown. Here, we performed fraction-resolved polysome profiling and characterized translational dynamics across oocytes and early embryo development. This approach allowed us to examine the changes in translation during pre-implantation development in high resolution and uncover previously unrecognized modes of translational selectivity. We observed a stage-specific delay in translation, characterized by the postponed recruitment of stored mRNAs-either unbound or associated with light ribosomal fractions-into actively translating polysomes (heavy fraction). Comparative analysis of translatome with proteomics, RNA N6-methyladenosine modifications, and mRNA features further revealed both coordinated and distinct regulatory mechanisms during pre-implantation development. Furthermore, we identified a eukaryotic initiation factor 1A domain containing 3, Eif1ad3, which is exclusively translated at the two-cell stage and is essential for embryonic development by regulating ribosome biogenesis and protein synthesis. Collectively, our study provides a valuable resource of spatiotemporal translational regulation in mammalian pre-implantation development and highlights a previously uncharacterized translation initiation factor critical for early embryos.</p>","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 18","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}