Pub Date : 2026-01-05DOI: 10.1038/s41594-025-01731-1
Kami Ahmad, Matt Wooten, Brittany N. Takushi, Velinda Vidaurre, Xin Chen, Steven Henikoff
In all eukaryotes, DNA replication is coupled to histone synthesis to coordinate chromatin packaging of the genome. Canonical histone genes coalesce in the nucleus into the histone locus body (HLB), where gene transcription and 3′ mRNA processing occurs. Both histone gene transcription and mRNA stability are reduced when DNA replication is inhibited, implying that the HLB senses the rate of DNA synthesis. In Drosophila melanogaster, the S-phase-induced histone genes are tandemly repeated in an ~100 copy array, whereas, in humans, these histone genes are scattered. In both organisms, these genes coalesce into HLBs. Here, we use a transgenic histone gene reporter and RNA interference in Drosophila to identify canonical H4 histone as a unique repressor of histone synthesis during the G2 phase in germline cells. Using cytology and CUT&Tag chromatin profiling, we find that histone H4 uniquely occupies histone gene promoters in both Drosophila and human cells. Our results suggest that repression of histone genes by soluble histone H4 is a conserved mechanism that coordinates DNA replication with histone synthesis in proliferating cells. Ahmad et al. show that soluble histone H4 binds at histone genes and acts as a repressor of their expression. These findings suggest that histone H4 is a sensor of ongoing DNA replication. Ongoing chromatin assembly uses up soluble H4 and relieves histone gene repression; however, once DNA replication ceases, soluble H4 accumulates and represses the histone genes.
{"title":"Cell-cycle-dependent repression of histone gene transcription by histone H4","authors":"Kami Ahmad, Matt Wooten, Brittany N. Takushi, Velinda Vidaurre, Xin Chen, Steven Henikoff","doi":"10.1038/s41594-025-01731-1","DOIUrl":"10.1038/s41594-025-01731-1","url":null,"abstract":"In all eukaryotes, DNA replication is coupled to histone synthesis to coordinate chromatin packaging of the genome. Canonical histone genes coalesce in the nucleus into the histone locus body (HLB), where gene transcription and 3′ mRNA processing occurs. Both histone gene transcription and mRNA stability are reduced when DNA replication is inhibited, implying that the HLB senses the rate of DNA synthesis. In Drosophila melanogaster, the S-phase-induced histone genes are tandemly repeated in an ~100 copy array, whereas, in humans, these histone genes are scattered. In both organisms, these genes coalesce into HLBs. Here, we use a transgenic histone gene reporter and RNA interference in Drosophila to identify canonical H4 histone as a unique repressor of histone synthesis during the G2 phase in germline cells. Using cytology and CUT&Tag chromatin profiling, we find that histone H4 uniquely occupies histone gene promoters in both Drosophila and human cells. Our results suggest that repression of histone genes by soluble histone H4 is a conserved mechanism that coordinates DNA replication with histone synthesis in proliferating cells. Ahmad et al. show that soluble histone H4 binds at histone genes and acts as a repressor of their expression. These findings suggest that histone H4 is a sensor of ongoing DNA replication. Ongoing chromatin assembly uses up soluble H4 and relieves histone gene repression; however, once DNA replication ceases, soluble H4 accumulates and represses the histone genes.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"145-156"},"PeriodicalIF":10.1,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01731-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902691","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 : 2026-01-05DOI: 10.1038/s41594-025-01733-z
Tommy O’Haren, Leila E. Rieder
The mechanisms that confine replication-dependent histone expression to S phase of the cell cycle remain unclear. Studies in Drosophila and cultured human cells show that non-nucleosomal histone H4 acts in a negative feedback loop to curtail histone gene expression at the end of S phase.
{"title":"A negative feedback mechanism controls histone gene expression","authors":"Tommy O’Haren, Leila E. Rieder","doi":"10.1038/s41594-025-01733-z","DOIUrl":"10.1038/s41594-025-01733-z","url":null,"abstract":"The mechanisms that confine replication-dependent histone expression to S phase of the cell cycle remain unclear. Studies in Drosophila and cultured human cells show that non-nucleosomal histone H4 acts in a negative feedback loop to curtail histone gene expression at the end of S phase.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"1-3"},"PeriodicalIF":10.1,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902692","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 : 2026-01-02DOI: 10.1038/s41594-025-01729-9
In this study, we applied single-particle cryogenic electron microscopy (cryo-EM) to native samples isolated from the human parasite Toxoplasma gondii, determining multiple structures of key components of the conoid, a cone-shaped organelle essential for host-cell invasion. We assigned 40 distinct proteins to the cryo-EM densities and uncovered their spatial organization and interactions.
{"title":"High-resolution cryo-EM meets parasitology in structural models of the conoid from Toxoplasma","authors":"","doi":"10.1038/s41594-025-01729-9","DOIUrl":"10.1038/s41594-025-01729-9","url":null,"abstract":"In this study, we applied single-particle cryogenic electron microscopy (cryo-EM) to native samples isolated from the human parasite Toxoplasma gondii, determining multiple structures of key components of the conoid, a cone-shaped organelle essential for host-cell invasion. We assigned 40 distinct proteins to the cryo-EM densities and uncovered their spatial organization and interactions.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"5-6"},"PeriodicalIF":10.1,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892958","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}
{"title":"Closing 2025, and a look ahead","authors":"","doi":"10.1038/s41594-025-01732-0","DOIUrl":"10.1038/s41594-025-01732-0","url":null,"abstract":"We review 2025 and discuss some of the foremost initiatives developed at the journal. We also look back at discoveries we have been proud to publish.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2373-2373"},"PeriodicalIF":10.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01732-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730583","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 : 2025-12-10DOI: 10.1038/s41594-025-01725-z
Ifigenia Tsitsa, Anja Conev, Alessia David, Suhail A. Islam, Michael J. E. Sternberg
The AlphaFold database, released in 2022, modeled UniProt sequences from April 2021 and now provides 200 million predicted protein structures. Of the 20,504 full-length predicted human structures, 631 entries conflict with the June 2025 UniProt release. Similar conflicts across species highlight how bioinformatics resources can rapidly age.
{"title":"The aging of the AlphaFold database","authors":"Ifigenia Tsitsa, Anja Conev, Alessia David, Suhail A. Islam, Michael J. E. Sternberg","doi":"10.1038/s41594-025-01725-z","DOIUrl":"10.1038/s41594-025-01725-z","url":null,"abstract":"The AlphaFold database, released in 2022, modeled UniProt sequences from April 2021 and now provides 200 million predicted protein structures. Of the 20,504 full-length predicted human structures, 631 entries conflict with the June 2025 UniProt release. Similar conflicts across species highlight how bioinformatics resources can rapidly age.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2374-2376"},"PeriodicalIF":10.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717909","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 : 2025-12-09DOI: 10.1038/s41594-025-01728-w
Jianwei Zeng, Yong Fu, Pengge Qian, Wei Huang, Qingwei Niu, Wandy L. Beatty, Alan Brown, L. David Sibley, Rui Zhang
Apicomplexan parasites, responsible for toxoplasmosis, cryptosporidiosis and malaria, invade host cells through a unique gliding motility mechanism powered by actomyosin motors and a dynamic organelle called the conoid. Here, using cryo-electron microscopy, we determined structures of four essential complexes of the Toxoplasma gondii conoid: the preconoidal P2 ring, tubulin-based conoid fibers, and the subpellicular and intraconoidal microtubules. Our analysis identified 40 distinct conoid proteins, several of which are essential for parasite lytic growth, as revealed through genetic disruption studies. Comparative analysis of the tubulin-containing complexes sheds light on their functional specialization by microtubule-associated proteins, while the structure of the preconoidal ring pinpoints the site of actin polymerization and initial translocation, enhancing our mechanistic understanding of gliding motility and, therefore, parasite invasion. Zeng et al. applied single-particle cryo-electron microscopy to native samples isolated from the human parasite Toxoplasma gondii, determining multiple structures of key components of the conoid, a cone-shaped organelle essential for host cell invasion.
{"title":"Atomic models of the Toxoplasma cell invasion machinery","authors":"Jianwei Zeng, Yong Fu, Pengge Qian, Wei Huang, Qingwei Niu, Wandy L. Beatty, Alan Brown, L. David Sibley, Rui Zhang","doi":"10.1038/s41594-025-01728-w","DOIUrl":"10.1038/s41594-025-01728-w","url":null,"abstract":"Apicomplexan parasites, responsible for toxoplasmosis, cryptosporidiosis and malaria, invade host cells through a unique gliding motility mechanism powered by actomyosin motors and a dynamic organelle called the conoid. Here, using cryo-electron microscopy, we determined structures of four essential complexes of the Toxoplasma gondii conoid: the preconoidal P2 ring, tubulin-based conoid fibers, and the subpellicular and intraconoidal microtubules. Our analysis identified 40 distinct conoid proteins, several of which are essential for parasite lytic growth, as revealed through genetic disruption studies. Comparative analysis of the tubulin-containing complexes sheds light on their functional specialization by microtubule-associated proteins, while the structure of the preconoidal ring pinpoints the site of actin polymerization and initial translocation, enhancing our mechanistic understanding of gliding motility and, therefore, parasite invasion. Zeng et al. applied single-particle cryo-electron microscopy to native samples isolated from the human parasite Toxoplasma gondii, determining multiple structures of key components of the conoid, a cone-shaped organelle essential for host cell invasion.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"157-170"},"PeriodicalIF":10.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01728-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705135","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 : 2025-12-07DOI: 10.1038/s41594-025-01734-y
Taylor L. Mighell, Ben Lehner
{"title":"Author Correction: A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR","authors":"Taylor L. Mighell, Ben Lehner","doi":"10.1038/s41594-025-01734-y","DOIUrl":"10.1038/s41594-025-01734-y","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2633-2633"},"PeriodicalIF":10.1,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01734-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701269","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 : 2025-12-03DOI: 10.1038/s41594-025-01724-0
Elizabeth T. Abshire, Lynne E. Maquat
The exon junction complex (EJC) begins to assemble on the spliceosome, which deposits EJCs upstream of most exon–exon junctions during pre-messenger RNA (mRNA) splicing. EJCs acquire additional alternative modules that define heterogeneous EJCs during pre-mRNA processing to mRNA in the nucleus and after mRNA export into the cytoplasm. In this Review, we discuss the mechanisms of EJC formation, the many roles of the EJC in pre-mRNA and mRNA regulation and how these roles are influenced by EJC composition. This Review summarizes the various functions of the exon junction complex in RNA splicing and beyond, to influence gene regulation.
{"title":"Gene regulation through exon junction complex modularity","authors":"Elizabeth T. Abshire, Lynne E. Maquat","doi":"10.1038/s41594-025-01724-0","DOIUrl":"10.1038/s41594-025-01724-0","url":null,"abstract":"The exon junction complex (EJC) begins to assemble on the spliceosome, which deposits EJCs upstream of most exon–exon junctions during pre-messenger RNA (mRNA) splicing. EJCs acquire additional alternative modules that define heterogeneous EJCs during pre-mRNA processing to mRNA in the nucleus and after mRNA export into the cytoplasm. In this Review, we discuss the mechanisms of EJC formation, the many roles of the EJC in pre-mRNA and mRNA regulation and how these roles are influenced by EJC composition. This Review summarizes the various functions of the exon junction complex in RNA splicing and beyond, to influence gene regulation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2387-2397"},"PeriodicalIF":10.1,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664342","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 : 2025-12-03DOI: 10.1038/s41594-025-01730-2
Ok-Ho Shin, Jun Lu, Jeong-Seop Rhee, Diana R. Tomchick, Zhiping P. Pang, Sonja M. Wojcik, Marcial Camacho-Perez, Nils Brose, Mischa Machius, Josep Rizo, Christian Rosenmund, Thomas C. Südhof
{"title":"Editorial Expression of Concern: Munc13 C2B domain is an activity-dependent Ca2+ regulator of synaptic exocytosis","authors":"Ok-Ho Shin, Jun Lu, Jeong-Seop Rhee, Diana R. Tomchick, Zhiping P. Pang, Sonja M. Wojcik, Marcial Camacho-Perez, Nils Brose, Mischa Machius, Josep Rizo, Christian Rosenmund, Thomas C. Südhof","doi":"10.1038/s41594-025-01730-2","DOIUrl":"10.1038/s41594-025-01730-2","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2634-2634"},"PeriodicalIF":10.1,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01730-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664012","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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