Pub Date : 2025-09-10DOI: 10.1038/s41594-025-01654-x
Transfer RNAs (tRNAs) are best known for their role in decoding messenger RNA codons and translating them into amino acids. A comprehensive biochemical and structural investigation of the poxviral transcription apparatus uncovers a thus far unknown role of specific host tRNAs as assembly chaperones for a multisubunit RNA polymerase complex.
{"title":"Host transfer RNA guides assembly of viral RNA polymerase","authors":"","doi":"10.1038/s41594-025-01654-x","DOIUrl":"10.1038/s41594-025-01654-x","url":null,"abstract":"Transfer RNAs (tRNAs) are best known for their role in decoding messenger RNA codons and translating them into amino acids. A comprehensive biochemical and structural investigation of the poxviral transcription apparatus uncovers a thus far unknown role of specific host tRNAs as assembly chaperones for a multisubunit RNA polymerase complex.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 11","pages":"2140-2141"},"PeriodicalIF":10.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031950","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 : 2025-09-09DOI: 10.1038/s41594-025-01679-2
Dimitris Typas
{"title":"A snapshot of proteostasis in human oocytes","authors":"Dimitris Typas","doi":"10.1038/s41594-025-01679-2","DOIUrl":"10.1038/s41594-025-01679-2","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1591-1591"},"PeriodicalIF":10.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018078","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 : 2025-09-09DOI: 10.1038/s41594-025-01663-w
Guifeng Wei, Heather Coker, Lisa Rodermund, Mafalda Almeida, Holly L. Roach, Tatyana B. Nesterova, Neil Brockdorff
X-chromosome inactivation (XCI) in mammals is orchestrated by the noncoding RNA X-inactive-specific transcript (Xist) that, together with specific interacting proteins, functions in cis to silence an entire X chromosome. Defined sites on Xist RNA carry the N6-methyladenosine (m6A) modification and perturbation of the m6A writer complex has been found to abrogate Xist-mediated gene silencing. However, the relative contribution of m6A and its mechanism of action remain unclear. Here we investigate the role of m6A in XCI by applying rapid degron-mediated depletion of METTL3, the catalytic subunit of the m6A writer complex, an approach that minimizes indirect effects because of transcriptome-wide depletion of m6A. We find that acute loss of METTL3 and m6A accelerates Xist-mediated gene silencing and this correlates with increased levels and stability of Xist transcripts. We show that Xist RNA turnover is mediated by the nuclear exosome targeting complex but is independent of the principal nuclear m6A reader protein YTHDC1. Our findings demonstrate that the primary function of m6A on Xist RNA is to promote Xist RNA turnover, which in turn regulates XCI dynamics. Wei et al. show that the primary function of m6A on the nuclear long noncoding RNA Xist, a master regulator of X inactivation, is to promote RNA degradation. Xist turnover is mediated by the nuclear exosome targeting complex and occurs independently of the nuclear m6A reader YTHDC1.
{"title":"m6A and the NEXT complex direct Xist RNA turnover and X-inactivation dynamics","authors":"Guifeng Wei, Heather Coker, Lisa Rodermund, Mafalda Almeida, Holly L. Roach, Tatyana B. Nesterova, Neil Brockdorff","doi":"10.1038/s41594-025-01663-w","DOIUrl":"10.1038/s41594-025-01663-w","url":null,"abstract":"X-chromosome inactivation (XCI) in mammals is orchestrated by the noncoding RNA X-inactive-specific transcript (Xist) that, together with specific interacting proteins, functions in cis to silence an entire X chromosome. Defined sites on Xist RNA carry the N6-methyladenosine (m6A) modification and perturbation of the m6A writer complex has been found to abrogate Xist-mediated gene silencing. However, the relative contribution of m6A and its mechanism of action remain unclear. Here we investigate the role of m6A in XCI by applying rapid degron-mediated depletion of METTL3, the catalytic subunit of the m6A writer complex, an approach that minimizes indirect effects because of transcriptome-wide depletion of m6A. We find that acute loss of METTL3 and m6A accelerates Xist-mediated gene silencing and this correlates with increased levels and stability of Xist transcripts. We show that Xist RNA turnover is mediated by the nuclear exosome targeting complex but is independent of the principal nuclear m6A reader protein YTHDC1. Our findings demonstrate that the primary function of m6A on Xist RNA is to promote Xist RNA turnover, which in turn regulates XCI dynamics. Wei et al. show that the primary function of m6A on the nuclear long noncoding RNA Xist, a master regulator of X inactivation, is to promote RNA degradation. Xist turnover is mediated by the nuclear exosome targeting complex and occurs independently of the nuclear m6A reader YTHDC1.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 11","pages":"2242-2251"},"PeriodicalIF":10.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01663-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018088","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 : 2025-09-08DOI: 10.1038/s41594-025-01651-0
Chatrin Chatrin, Kang Zhu, Ivan Ahel
Post-translational modifications show mechanistic crosstalk, exemplified by the ADP-ribose–ubiquitin hybrid signal, in which one post-translational modification modifies another. This Comment highlights its discovery, mechanistic basis and functional consequences, and outlines critical questions for understanding this emerging signaling paradigm.
{"title":"The rise of ADP-ribose–ubiquitin","authors":"Chatrin Chatrin, Kang Zhu, Ivan Ahel","doi":"10.1038/s41594-025-01651-0","DOIUrl":"10.1038/s41594-025-01651-0","url":null,"abstract":"Post-translational modifications show mechanistic crosstalk, exemplified by the ADP-ribose–ubiquitin hybrid signal, in which one post-translational modification modifies another. This Comment highlights its discovery, mechanistic basis and functional consequences, and outlines critical questions for understanding this emerging signaling paradigm.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1582-1585"},"PeriodicalIF":10.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009278","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 : 2025-09-08DOI: 10.1038/s41594-025-01670-x
We developed an efficient transposon-based approach to create a panel of large genomic rearrangements between lamina associated domains (LADs) and inter-LAD sequences. This work demonstrates that LAD–nuclear lamina interactions involve multiple contacts of varying strength. Moreover, changes in nuclear lamina association are often accompanied by transcriptional repression and heterochromatin histone mark deposition.
{"title":"Redundant and cooperative interactions between the genome and nuclear lamina","authors":"","doi":"10.1038/s41594-025-01670-x","DOIUrl":"10.1038/s41594-025-01670-x","url":null,"abstract":"We developed an efficient transposon-based approach to create a panel of large genomic rearrangements between lamina associated domains (LADs) and inter-LAD sequences. This work demonstrates that LAD–nuclear lamina interactions involve multiple contacts of varying strength. Moreover, changes in nuclear lamina association are often accompanied by transcriptional repression and heterochromatin histone mark deposition.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 11","pages":"2138-2139"},"PeriodicalIF":10.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018079","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 : 2025-09-04DOI: 10.1038/s41594-025-01653-y
Julia Bartuli, Stefan Jungwirth, Manisha Dixit, Takumi Okuda, Johannes Patrick Zimmermann, Matthias Erlacher, Tao Pan, Asisa Volz, Alexander Hüttenhofer, Bettina Warscheid, Claudia Höbartner, Clemens Grimm, Utz Fischer
Transfer RNAs (tRNAs) are widely recognized for their role in translation. Here, we describe a previously unidentified function of tRNA as an assembly chaperone. During poxviral infection, tRNAGln/Arg lacking the anticodon mcm5s2U34 modification is specifically sequestered from the cellular tRNA pool to promote formation of a multisubunit poxviral RNA polymerase complex (vRNAP). Cryo-electron microscopy analysis of assembly intermediates illustrates how tRNAGln/Arg orchestrates the recruitment of transcription and mRNA processing factors to vRNAP where it controls the transition to the preinitiation complex. This is achieved by an induced fit mechanism that internalizes anticodon base G36 into the anticodon stem, creating a noncanonical tRNA structure and selecting a defined tRNA modification pattern. The role of tRNA as an assembly chaperone extends to the pathogenic Mpox virus, which features a similar vRNAP. Here, the authors solve a series of cryo-electron microscopy structures that show how transfer RNAs (tRNAs) can guide the assembly of the multisubunit poxvirus RNA polymerase, uncovering a role of tRNA as an assembly chaperone.
{"title":"tRNA as an assembly chaperone for a macromolecular transcription-processing complex","authors":"Julia Bartuli, Stefan Jungwirth, Manisha Dixit, Takumi Okuda, Johannes Patrick Zimmermann, Matthias Erlacher, Tao Pan, Asisa Volz, Alexander Hüttenhofer, Bettina Warscheid, Claudia Höbartner, Clemens Grimm, Utz Fischer","doi":"10.1038/s41594-025-01653-y","DOIUrl":"10.1038/s41594-025-01653-y","url":null,"abstract":"Transfer RNAs (tRNAs) are widely recognized for their role in translation. Here, we describe a previously unidentified function of tRNA as an assembly chaperone. During poxviral infection, tRNAGln/Arg lacking the anticodon mcm5s2U34 modification is specifically sequestered from the cellular tRNA pool to promote formation of a multisubunit poxviral RNA polymerase complex (vRNAP). Cryo-electron microscopy analysis of assembly intermediates illustrates how tRNAGln/Arg orchestrates the recruitment of transcription and mRNA processing factors to vRNAP where it controls the transition to the preinitiation complex. This is achieved by an induced fit mechanism that internalizes anticodon base G36 into the anticodon stem, creating a noncanonical tRNA structure and selecting a defined tRNA modification pattern. The role of tRNA as an assembly chaperone extends to the pathogenic Mpox virus, which features a similar vRNAP. Here, the authors solve a series of cryo-electron microscopy structures that show how transfer RNAs (tRNAs) can guide the assembly of the multisubunit poxvirus RNA polymerase, uncovering a role of tRNA as an assembly chaperone.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 11","pages":"2349-2358"},"PeriodicalIF":10.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01653-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983399","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 : 2025-09-02DOI: 10.1038/s41594-025-01664-9
Yi-Lan Chen, Jin-Der Wen
To start, or not to start, that is the recurring question faced by eukaryotic ribosomes as they scan mRNA for translation start sites. A study now shows that two opposing initiation factors, which bind the ribosome in a mutually exclusive manner, assist in this decision-making process.
{"title":"Two dynamically competing factors determine the translation start site","authors":"Yi-Lan Chen, Jin-Der Wen","doi":"10.1038/s41594-025-01664-9","DOIUrl":"10.1038/s41594-025-01664-9","url":null,"abstract":"To start, or not to start, that is the recurring question faced by eukaryotic ribosomes as they scan mRNA for translation start sites. A study now shows that two opposing initiation factors, which bind the ribosome in a mutually exclusive manner, assist in this decision-making process.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 11","pages":"2134-2135"},"PeriodicalIF":10.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928368","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 : 2025-09-02DOI: 10.1038/s41594-025-01661-y
Ane Iturbide, Mayra L. Ruiz Tejada Segura, Camille Noll, Kenji Schorpp, Ina Rothenaigner, Elias R. Ruiz-Morales, Gabriele Lubatti, Ahmed Agami, Kamyar Hadian, Antonio Scialdone, Maria-Elena Torres-Padilla
{"title":"Addendum: Retinoic acid signaling is critical during the totipotency window in early mammalian development","authors":"Ane Iturbide, Mayra L. Ruiz Tejada Segura, Camille Noll, Kenji Schorpp, Ina Rothenaigner, Elias R. Ruiz-Morales, Gabriele Lubatti, Ahmed Agami, Kamyar Hadian, Antonio Scialdone, Maria-Elena Torres-Padilla","doi":"10.1038/s41594-025-01661-y","DOIUrl":"10.1038/s41594-025-01661-y","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 10","pages":"2128-2129"},"PeriodicalIF":10.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01661-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961730","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 : 2025-09-01DOI: 10.1038/s41594-025-01655-w
Lise Dauban, Mathias Eder, Marcel de Haas, Vinícius H. Franceschini-Santos, J. Omar Yañez-Cuna, Moreno Martinovic, Tom van Schaik, Christ Leemans, Hans Teunissen, Koen Rademaker, Miguel Martinez Ara, Martijn Verkuilen, Elzo de Wit, Bas van Steensel
Lamina-associated domains (LADs) are megabase-sized genomic regions that interact with the nuclear lamina (NL). It is not yet understood how their interactions with the NL are encoded in their DNA. Here we designed an efficient LAD ‘scrambling’ approach, based on transposon-mediated local hopping of loxP recombination sites, to generate series of large deletions and inversions that span LADs and flanking sequences. Mapping of NL interactions in these rearrangements revealed that, in mouse embryonic stem cells, a single LAD contacts the NL through multiple regions that act cooperatively or redundantly; some have more affinity for the NL than others and can pull neighboring sequences to the NL. Genes drawn toward the NL showed often but not always reduced expression and increased H3K9me3 levels. Furthermore, neighboring LADs can cooperatively interact with the NL when placed close enough to each other. These results elucidate principles that govern the positioning of megabase-sized genomic regions inside the cell nucleus. Using a transposon-based approach to create a set of large genomic rearrangements, Dauban et al. demonstrate that interactions of lamina-associated domains with the nuclear lamina involve multiple contacts of varying strength.
{"title":"Interactions between the genome and the nuclear lamina are multivalent and cooperative","authors":"Lise Dauban, Mathias Eder, Marcel de Haas, Vinícius H. Franceschini-Santos, J. Omar Yañez-Cuna, Moreno Martinovic, Tom van Schaik, Christ Leemans, Hans Teunissen, Koen Rademaker, Miguel Martinez Ara, Martijn Verkuilen, Elzo de Wit, Bas van Steensel","doi":"10.1038/s41594-025-01655-w","DOIUrl":"10.1038/s41594-025-01655-w","url":null,"abstract":"Lamina-associated domains (LADs) are megabase-sized genomic regions that interact with the nuclear lamina (NL). It is not yet understood how their interactions with the NL are encoded in their DNA. Here we designed an efficient LAD ‘scrambling’ approach, based on transposon-mediated local hopping of loxP recombination sites, to generate series of large deletions and inversions that span LADs and flanking sequences. Mapping of NL interactions in these rearrangements revealed that, in mouse embryonic stem cells, a single LAD contacts the NL through multiple regions that act cooperatively or redundantly; some have more affinity for the NL than others and can pull neighboring sequences to the NL. Genes drawn toward the NL showed often but not always reduced expression and increased H3K9me3 levels. Furthermore, neighboring LADs can cooperatively interact with the NL when placed close enough to each other. These results elucidate principles that govern the positioning of megabase-sized genomic regions inside the cell nucleus. Using a transposon-based approach to create a set of large genomic rearrangements, Dauban et al. demonstrate that interactions of lamina-associated domains with the nuclear lamina involve multiple contacts of varying strength.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 11","pages":"2335-2348"},"PeriodicalIF":10.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01655-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144924213","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 : 2025-08-29DOI: 10.1038/s41594-025-01667-6
Nadine Renner, Alex Kleinpeter, Donna L. Mallery, Anna Albecka, K. M. Rifat Faysal, Till Böcking, Adolfo Saiardi, Eric O. Freed, Leo C. James
{"title":"Author Correction: HIV-1 is dependent on its immature lattice to recruit IP6 for mature capsid assembly","authors":"Nadine Renner, Alex Kleinpeter, Donna L. Mallery, Anna Albecka, K. M. Rifat Faysal, Till Böcking, Adolfo Saiardi, Eric O. Freed, Leo C. James","doi":"10.1038/s41594-025-01667-6","DOIUrl":"10.1038/s41594-025-01667-6","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1839-1839"},"PeriodicalIF":10.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01667-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961744","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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