Pub Date : 2026-02-18DOI: 10.1038/s41594-026-01768-w
In this issue of Nature Structural & Molecular Biology, we are publishing two studies investigating the mechanisms of how bacteria fight phage invasion, and how phages fight back.
{"title":"The phage–bacteria arms race","authors":"","doi":"10.1038/s41594-026-01768-w","DOIUrl":"10.1038/s41594-026-01768-w","url":null,"abstract":"In this issue of Nature Structural & Molecular Biology, we are publishing two studies investigating the mechanisms of how bacteria fight phage invasion, and how phages fight back.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 2","pages":"193-193"},"PeriodicalIF":10.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01768-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-18DOI: 10.1038/s41594-026-01754-2
M. Jasnauskaitė, J. Juozapaitis, T. Liegutė, R. Grigaitis, A. Skorupskaitė, W. Steinchen, A. Mikšys, L. Truncaitė, K. Kazlauskaitė, M. F. Torres Jiménez, S. Khochare, G. Dudas, G. Bange, L. Malinauskaitė, I. Songailienė, P. Pausch
Retrons are prokaryotic reverse transcriptase systems that produce multicopy single-stranded DNA (msDNA), yet the principles by which they mediate antiviral defense remain largely unresolved. Here we investigate the mechanism of Escherichia coli Eco2, a minimal retron composed of a single reverse transcriptase–nuclease fusion protein. Cryogenic electron microscopy and hydrogen/deuterium exchange mass spectrometry reveal the structures and dynamics of a trimeric nucleoprotein complex assembled within a branched msDNA scaffold, which cages the TOPRIM nucleases. We show that the phage-encoded endonuclease DenB initiates msDNA degradation, thereby unblocking the nuclease active sites. Activated Eco2 cuts transfer RNAs, resulting in translational shutdown for antiphage defense. We further identify ribosomal protein S1 as a putative RNA chaperone that associates with the msDNA precursor. These findings provide insights into the molecular mechanisms of minimal retrons and establish a structural basis for engineering of Eco2. This study shows how the bacterial retron Eco2 defends against viruses. Phage nucleases trigger activation of Eco2, which cuts RNAs, shuts down protein production and stops phage replication.
{"title":"Structure and mechanism of antiphage retron Eco2","authors":"M. Jasnauskaitė, J. Juozapaitis, T. Liegutė, R. Grigaitis, A. Skorupskaitė, W. Steinchen, A. Mikšys, L. Truncaitė, K. Kazlauskaitė, M. F. Torres Jiménez, S. Khochare, G. Dudas, G. Bange, L. Malinauskaitė, I. Songailienė, P. Pausch","doi":"10.1038/s41594-026-01754-2","DOIUrl":"10.1038/s41594-026-01754-2","url":null,"abstract":"Retrons are prokaryotic reverse transcriptase systems that produce multicopy single-stranded DNA (msDNA), yet the principles by which they mediate antiviral defense remain largely unresolved. Here we investigate the mechanism of Escherichia coli Eco2, a minimal retron composed of a single reverse transcriptase–nuclease fusion protein. Cryogenic electron microscopy and hydrogen/deuterium exchange mass spectrometry reveal the structures and dynamics of a trimeric nucleoprotein complex assembled within a branched msDNA scaffold, which cages the TOPRIM nucleases. We show that the phage-encoded endonuclease DenB initiates msDNA degradation, thereby unblocking the nuclease active sites. Activated Eco2 cuts transfer RNAs, resulting in translational shutdown for antiphage defense. We further identify ribosomal protein S1 as a putative RNA chaperone that associates with the msDNA precursor. These findings provide insights into the molecular mechanisms of minimal retrons and establish a structural basis for engineering of Eco2. This study shows how the bacterial retron Eco2 defends against viruses. Phage nucleases trigger activation of Eco2, which cuts RNAs, shuts down protein production and stops phage replication.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 2","pages":"330-340"},"PeriodicalIF":10.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01754-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-16DOI: 10.1038/s41594-025-01739-7
Chinmai Pindi, Giulia Palermo
Genome editing with CRISPR–Cas systems is revolutionizing medicine, molecular biology and biotechnology. In this Review, we discuss the contributions of deep learning-based structure prediction algorithms, physics-based simulations, neural networks, graph neural networks and generative models, including diffusion and large language models, in engineering and optimizing CRISPR systems and in understanding their mechanistic basis. We highlight the challenges and limitations to the transformative effects of computational modeling and tools in the context of the development of programmable genome editors for biomedicine and biotechnology. Pindi and Palermo review the contributions of deep learning structure prediction algorithms, physics-based simulations, neural networks, graph neural networks and generative models in engineering CRISPR systems and in understanding their mechanistic basis.
{"title":"Computation and deep-learning-driven advances in CRISPR genome editing","authors":"Chinmai Pindi, Giulia Palermo","doi":"10.1038/s41594-025-01739-7","DOIUrl":"10.1038/s41594-025-01739-7","url":null,"abstract":"Genome editing with CRISPR–Cas systems is revolutionizing medicine, molecular biology and biotechnology. In this Review, we discuss the contributions of deep learning-based structure prediction algorithms, physics-based simulations, neural networks, graph neural networks and generative models, including diffusion and large language models, in engineering and optimizing CRISPR systems and in understanding their mechanistic basis. We highlight the challenges and limitations to the transformative effects of computational modeling and tools in the context of the development of programmable genome editors for biomedicine and biotechnology. Pindi and Palermo review the contributions of deep learning structure prediction algorithms, physics-based simulations, neural networks, graph neural networks and generative models in engineering CRISPR systems and in understanding their mechanistic basis.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 2","pages":"203-214"},"PeriodicalIF":10.1,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-11DOI: 10.1038/s41594-026-01745-3
Julie Soutourina
Transcription is tightly regulated and universal across all domains of life. A study proposes how, during eukaryotic evolution, the emergence of a regulatory mechanism consisting of a focused promoter-proximal pause of RNA polymerase II could have originated from a proto-pause with the acquisition of negative elongation factor (NELF) subunits.
{"title":"Promoter proximal pausing of RNA polymerase across evolution","authors":"Julie Soutourina","doi":"10.1038/s41594-026-01745-3","DOIUrl":"10.1038/s41594-026-01745-3","url":null,"abstract":"Transcription is tightly regulated and universal across all domains of life. A study proposes how, during eukaryotic evolution, the emergence of a regulatory mechanism consisting of a focused promoter-proximal pause of RNA polymerase II could have originated from a proto-pause with the acquisition of negative elongation factor (NELF) subunits.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 2","pages":"195-197"},"PeriodicalIF":10.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-10DOI: 10.1038/s41594-025-01740-0
Mingxu Fang, Yajie Gu, Miron Leanca, Mariusz Matyszewski, Andy LiWang, Yulia Yuzenkova, Kevin D. Corbett, Susan S. Golden
Circadian biological clocks evolved across kingdoms of life as an adaptation to predictable cycles of sunrise and sunset. In the cyanobacterium Synechococcus elongatus, a protein-based clock precisely controls when different genes are turned on and off during the 24-h day but the phasing mechanism remains unclear. Here we show the molecular basis of this regulation and reconstitute clock-controlled transcription in vitro using purified components. Biochemical and structural analyses revealed that the clock-regulated transcription factor RpaA can function as either an activator or a repressor of cyanobacterial RNA polymerase, depending on its binding position relative to core promoter elements. Leveraging the repressor mechanism, we developed a heterologous in vitro system driven by bacteriophage T7 RNA polymerase that sustains circadian transcription for multiple days. These findings explain how a single clock output generates opposite phases of gene expression and define the minimal components for circadian clock function, enabling synthetic or biotechnological applications. Fang et al. reveal how a bacterial circadian clock turns genes on and off at the right times of day and use the purified proteins to drive circadian gene transcription in a test tube for days.
{"title":"Mechanism and reconstitution of circadian transcription in cyanobacteria","authors":"Mingxu Fang, Yajie Gu, Miron Leanca, Mariusz Matyszewski, Andy LiWang, Yulia Yuzenkova, Kevin D. Corbett, Susan S. Golden","doi":"10.1038/s41594-025-01740-0","DOIUrl":"10.1038/s41594-025-01740-0","url":null,"abstract":"Circadian biological clocks evolved across kingdoms of life as an adaptation to predictable cycles of sunrise and sunset. In the cyanobacterium Synechococcus elongatus, a protein-based clock precisely controls when different genes are turned on and off during the 24-h day but the phasing mechanism remains unclear. Here we show the molecular basis of this regulation and reconstitute clock-controlled transcription in vitro using purified components. Biochemical and structural analyses revealed that the clock-regulated transcription factor RpaA can function as either an activator or a repressor of cyanobacterial RNA polymerase, depending on its binding position relative to core promoter elements. Leveraging the repressor mechanism, we developed a heterologous in vitro system driven by bacteriophage T7 RNA polymerase that sustains circadian transcription for multiple days. These findings explain how a single clock output generates opposite phases of gene expression and define the minimal components for circadian clock function, enabling synthetic or biotechnological applications. Fang et al. reveal how a bacterial circadian clock turns genes on and off at the right times of day and use the purified proteins to drive circadian gene transcription in a test tube for days.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 2","pages":"275-281"},"PeriodicalIF":10.1,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01740-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA-guided DNA nucleases Cas9 and IscB (insertion sequences Cas9-like OrfB) are components of type II CRISPR–Cas adaptive immune systems and transposon-associated OMEGA (obligate mobile element-guided activity) systems, respectively. Sequence and structural comparisons indicate that IscB (~500 residues) evolved into Cas9 (~700–1,600 residues) through protein expansion coupled with guide RNA miniaturization. However, the specific sequence of events in this evolutionary transition remains unknown. Here, we report cryo-electron microscopy structures of four phylogenetically diverse RNA-guided nucleases—two IscBs and two Cas9s—each in complex with its cognate guide RNA and target DNA. Comparisons of these four complex structures to previously reported IscB and Cas9 structures indicate that evolution from IscB to Cas9 involved the loss of the N-terminal PLMP domain and the acquisition of the zinc-finger-containing REC3 domain, followed by bridge helix extension and REC1 domain acquisition. These structural changes led to expansion of the REC lobe, increasing the target DNA cleavage specificity. Additionally, the structural conservation of the RNA scaffolds indicates that the dual CRISPR RNA (crRNA) and trans-activating crRNA guides of CRISPR–Cas9 evolved from the single ωRNA guides of OMEGA systems. Our findings provide insights into the succession of structural changes involved in the exaptation of transposon-associated RNA-guided nucleases for the role of effector nucleases in adaptive immune systems. Nagahata, Kato and Yamada et al. provide cryo-electron microscopy structures of four phylogenetically diverse RNA-guided nucleases—HfmIscB, TbaIscB, YnpsCas9 and NbaCas9—each in complex with its guide RNA and target DNA, providing insights into CRISPR–Cas9 evolution.
{"title":"Structural visualization of the molecular evolution of CRISPR–Cas9","authors":"Naoto Nagahata, Kazuki Kato, Sota Yamada, Soumya Kannan, Sae Okazaki, Yukari Isayama, Masahiro Hiraizumi, Keitaro Yamashita, Eugene V. Koonin, Feng Zhang, Hiroshi Nishimasu","doi":"10.1038/s41594-025-01743-x","DOIUrl":"10.1038/s41594-025-01743-x","url":null,"abstract":"RNA-guided DNA nucleases Cas9 and IscB (insertion sequences Cas9-like OrfB) are components of type II CRISPR–Cas adaptive immune systems and transposon-associated OMEGA (obligate mobile element-guided activity) systems, respectively. Sequence and structural comparisons indicate that IscB (~500 residues) evolved into Cas9 (~700–1,600 residues) through protein expansion coupled with guide RNA miniaturization. However, the specific sequence of events in this evolutionary transition remains unknown. Here, we report cryo-electron microscopy structures of four phylogenetically diverse RNA-guided nucleases—two IscBs and two Cas9s—each in complex with its cognate guide RNA and target DNA. Comparisons of these four complex structures to previously reported IscB and Cas9 structures indicate that evolution from IscB to Cas9 involved the loss of the N-terminal PLMP domain and the acquisition of the zinc-finger-containing REC3 domain, followed by bridge helix extension and REC1 domain acquisition. These structural changes led to expansion of the REC lobe, increasing the target DNA cleavage specificity. Additionally, the structural conservation of the RNA scaffolds indicates that the dual CRISPR RNA (crRNA) and trans-activating crRNA guides of CRISPR–Cas9 evolved from the single ωRNA guides of OMEGA systems. Our findings provide insights into the succession of structural changes involved in the exaptation of transposon-associated RNA-guided nucleases for the role of effector nucleases in adaptive immune systems. Nagahata, Kato and Yamada et al. provide cryo-electron microscopy structures of four phylogenetically diverse RNA-guided nucleases—HfmIscB, TbaIscB, YnpsCas9 and NbaCas9—each in complex with its guide RNA and target DNA, providing insights into CRISPR–Cas9 evolution.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 2","pages":"304-317"},"PeriodicalIF":10.1,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1038/s41594-026-01744-4
Xiaogen Zhou, Xiangyu Xu, Guijun Zhang
Accurately interpreting density maps into atomic models is a central yet challenging goal of cryo-EM. Two studies now reveal distinct ways in which protein structure prediction can be incorporated into cryo-EM model building to enable more accurate and robust automated construction of protein atomic models from density maps.
{"title":"When cryo-EM modeling meets structure prediction","authors":"Xiaogen Zhou, Xiangyu Xu, Guijun Zhang","doi":"10.1038/s41594-026-01744-4","DOIUrl":"10.1038/s41594-026-01744-4","url":null,"abstract":"Accurately interpreting density maps into atomic models is a central yet challenging goal of cryo-EM. Two studies now reveal distinct ways in which protein structure prediction can be incorporated into cryo-EM model building to enable more accurate and robust automated construction of protein atomic models from density maps.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 2","pages":"200-202"},"PeriodicalIF":10.1,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1038/s41594-025-01737-9
Nataliya Petryk
For Okazaki fragments to efficiently mature, RNA primers need to be removed. A recent study in Nature Structural & Molecular Biology implicates ADAR1 in editing mismatched primers to promote unabated lagging-strand synthesis, via oxidation-dependent dimerization and activation of ADAR1.
{"title":"ADAR1 is an editor of DNA replication forks","authors":"Nataliya Petryk","doi":"10.1038/s41594-025-01737-9","DOIUrl":"10.1038/s41594-025-01737-9","url":null,"abstract":"For Okazaki fragments to efficiently mature, RNA primers need to be removed. A recent study in Nature Structural & Molecular Biology implicates ADAR1 in editing mismatched primers to promote unabated lagging-strand synthesis, via oxidation-dependent dimerization and activation of ADAR1.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 2","pages":"198-199"},"PeriodicalIF":10.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1038/s41594-026-01748-0
Ben L. Carty, Danilo Dubocanin, Marina Murillo-Pineda, Marie Dumont, Emilia Volpe, Pawel Mikulski, Julia Humes, Oliver Whittingham, Daniele Fachinetti, Simona Giunta, Nicolas Altemose, Lars E. T. Jansen
{"title":"Author Correction: Heterochromatin boundaries maintain centromere position, size and number","authors":"Ben L. Carty, Danilo Dubocanin, Marina Murillo-Pineda, Marie Dumont, Emilia Volpe, Pawel Mikulski, Julia Humes, Oliver Whittingham, Daniele Fachinetti, Simona Giunta, Nicolas Altemose, Lars E. T. Jansen","doi":"10.1038/s41594-026-01748-0","DOIUrl":"10.1038/s41594-026-01748-0","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 2","pages":"362-362"},"PeriodicalIF":10.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01748-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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