Nature structural & molecular biology最新文献

RapA opens the RNA polymerase clamp to disrupt post-termination complexes and prevent cytotoxic R-loop formation

Nature structural & molecular biology Pub Date : 2025-01-08 DOI: 10.1038/s41594-024-01447-8

Joshua J. Brewer, Koe Inlow, Rachel A. Mooney, Barbara Bosch, Paul Dominic B. Olinares, Leandro Pimentel Marcelino, Brian T. Chait, Robert Landick, Jeff Gelles, Elizabeth A. Campbell, Seth A. Darst

{"title":"RapA opens the RNA polymerase clamp to disrupt post-termination complexes and prevent cytotoxic R-loop formation","authors":"Joshua J. Brewer, Koe Inlow, Rachel A. Mooney, Barbara Bosch, Paul Dominic B. Olinares, Leandro Pimentel Marcelino, Brian T. Chait, Robert Landick, Jeff Gelles, Elizabeth A. Campbell, Seth A. Darst","doi":"10.1038/s41594-024-01447-8","DOIUrl":"https://doi.org/10.1038/s41594-024-01447-8","url":null,"abstract":"Following transcript release during intrinsic termination, Escherichia coli RNA polymerase (RNAP) often remains associated with DNA in a post-termination complex (PTC). RNAPs in PTCs are removed from the DNA by the SWI2/SNF2 adenosine triphosphatase (ATPase) RapA. Here we determined PTC structures on negatively supercoiled DNA and with RapA engaged to dislodge the PTC. We found that core RNAP in the PTC can unwind DNA and initiate RNA synthesis but is prone to producing R-loops. Nucleotide binding to RapA triggers a conformational change that opens the RNAP clamp, allowing DNA in the RNAP cleft to reanneal and dissociate. We show that RapA helps to control cytotoxic R-loop formation in vivo, likely by disrupting PTCs. We suggest that analogous ATPases acting on PTCs to suppress transcriptional noise and R-loop formation may be widespread. These results hold importance for the bacterial transcription cycle and highlight a role for RapA in maintaining genome stability.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"80 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II

Nature structural & molecular biology Pub Date : 2025-01-08 DOI: 10.1038/s41594-024-01453-w

Yixuan Pan, Meiyang Liu, Chun Ruan, Mengyuan Peng, Min Hao, Qi Zhang, Jingdong Xue, Yanling Niu, Ningzhe Li, Haipeng Guan, Pei Wang, Mingqian Hu, Haitao Li, Wenjuan Wang, Juan Song, Yanhua Yao, Yimin Lao, Bing Li

{"title":"Inherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II","authors":"Yixuan Pan, Meiyang Liu, Chun Ruan, Mengyuan Peng, Min Hao, Qi Zhang, Jingdong Xue, Yanling Niu, Ningzhe Li, Haipeng Guan, Pei Wang, Mingqian Hu, Haitao Li, Wenjuan Wang, Juan Song, Yanhua Yao, Yimin Lao, Bing Li","doi":"10.1038/s41594-024-01453-w","DOIUrl":"https://doi.org/10.1038/s41594-024-01453-w","url":null,"abstract":"The Rpd3S histone deacetylase complex has a crucial role in genomic integrity by deacetylating transcribed nucleosomes following RNA polymerase (Pol) II passage. Cryo-EM studies highlight the importance of asymmetrical Rco1–Eaf3 dimers in nucleosome binding, yet the interaction dynamics with nucleosomal substrates alongside elongating Pol II are poorly understood. Here we demonstrate the essential function of the Rco1 N-terminal intrinsically disordered region (IDR) in modulating Pol II association, in which K/R mutations within the Rco1 IDR impair interaction of Rpd3S with the C-terminal domain (CTD) of Rpb1, without affecting nucleosome recognition or complex integrity. We also identify the Rco1-PHD1 and Eaf3-CHD domains as crucial for specific binding to Ser5-phosphorylated CTD. The Rco1 IDR alleviates autoinhibition from its C terminus, facilitating PHD1-CHD engagement with phosphorylated CTD. Furthermore, we reveal a conserved mechanism by which asymmetrical Rco1–Eaf3 dimers coordinate nucleosome engagement and Pol II interaction, enhancing understanding of epigenetic complexes associated with transcriptional machinery.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Importance of an N-terminal structural switch in the distinction between small RNA-bound and free ARGONAUTE

Nature structural & molecular biology Pub Date : 2025-01-07 DOI: 10.1038/s41594-024-01446-9

Simon Bressendorff, Ida Marie Zobbe Sjøgaard, Andreas Prestel, Vasileios Voutsinos, Martin D. Jansson, Patrice Ménard, Anders H. Lund, Rasmus Hartmann-Petersen, Birthe B. Kragelund, Christian Poulsen, Peter Brodersen

{"title":"Importance of an N-terminal structural switch in the distinction between small RNA-bound and free ARGONAUTE","authors":"Simon Bressendorff, Ida Marie Zobbe Sjøgaard, Andreas Prestel, Vasileios Voutsinos, Martin D. Jansson, Patrice Ménard, Anders H. Lund, Rasmus Hartmann-Petersen, Birthe B. Kragelund, Christian Poulsen, Peter Brodersen","doi":"10.1038/s41594-024-01446-9","DOIUrl":"https://doi.org/10.1038/s41594-024-01446-9","url":null,"abstract":"ARGONAUTE (AGO) proteins bind to small non-coding RNAs to form RNA-induced silencing complexes. In the RNA-bound state, AGO is stable while RNA-free AGO turns over rapidly. Molecular features unique to RNA-free AGO that allow its specific recognition and degradation remain unknown. Here, we identify a confined, linear region in Arabidopsis AGO1 and human Ago2, the N-coil, as a structural switch with preferential accessibility in the RNA-free state. RNA-free Arabidopsis AGO1 interacts with the autophagy cargo receptor ATI1 by direct contact with specific N-coil amino acid residues whose mutation reduces the degradation rate of RNA-free AGO1 in vivo. The N-coil of human Ago2 has similar degron activity dependent on residues in positions equivalent to those required for the Arabidopsis AGO1–ATI1 interaction. These results elucidate the molecular basis for specific recognition and degradation of the RNA-free state of eukaryotic AGO proteins.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications

Nature structural & molecular biology Pub Date : 2025-01-07 DOI: 10.1038/s41594-024-01452-x

Trinity Cookis, Alexandria Lydecker, Paul Sauer, Vignesh Kasinath, Eva Nogales

引用次数: 0

Capture, mutual inhibition and release mechanism for aPKC–Par6 and its multisite polarity substrate Lgl

Nature structural & molecular biology Pub Date : 2025-01-06 DOI: 10.1038/s41594-024-01425-0

Christopher P. Earl, Mathias Cobbaut, André Barros-Carvalho, Marina E. Ivanova, David C. Briggs, Eurico Morais-de-Sá, Peter J. Parker, Neil Q. McDonald

{"title":"Capture, mutual inhibition and release mechanism for aPKC–Par6 and its multisite polarity substrate Lgl","authors":"Christopher P. Earl, Mathias Cobbaut, André Barros-Carvalho, Marina E. Ivanova, David C. Briggs, Eurico Morais-de-Sá, Peter J. Parker, Neil Q. McDonald","doi":"10.1038/s41594-024-01425-0","DOIUrl":"https://doi.org/10.1038/s41594-024-01425-0","url":null,"abstract":"The mutually antagonistic relationship of atypical protein kinase C (aPKC) and partitioning-defective protein 6 (Par6) with the substrate lethal (2) giant larvae (Lgl) is essential for regulating polarity across many cell types. Although aPKC–Par6 phosphorylates Lgl at three serine sites to exclude it from the apical domain, aPKC–Par6 and Lgl paradoxically form a stable kinase–substrate complex, with conflicting roles proposed for Par6. We report the structure of human aPKCι–Par6α bound to full-length Llgl1, captured through an aPKCι docking site and a Par6PDZ contact. This complex traps a phospho-S663 Llgl1 intermediate bridging between aPKC and Par6, impeding phosphorylation progression. Thus, aPKCι is effectively inhibited by Llgl1pS663 while Llgl1 is captured by aPKCι–Par6. Mutational disruption of the Lgl–aPKC interaction impedes complex assembly and Lgl phosphorylation, whereas disrupting the Lgl–Par6PDZ contact promotes complex dissociation and Lgl phosphorylation. We demonstrate a Par6PDZ-regulated substrate capture-and-release model requiring binding by active Cdc42 and the apical partner Crumbs to drive complex disassembly. Our results suggest a mechanism for mutual regulation and spatial control of aPKC–Par6 and Lgl activities.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanism of mammalian transcriptional repression by noncoding RNA

Nature structural & molecular biology Pub Date : 2025-01-06 DOI: 10.1038/s41594-024-01448-7

Katarína Tlučková, Beata Kaczmarek, Anita Salmazo, Carrie Bernecky

引用次数: 0

ATM and IRAK1 orchestrate two distinct mechanisms of NF-κB activation in response to DNA damage

Nature structural & molecular biology Pub Date : 2025-01-03 DOI: 10.1038/s41594-024-01417-0

Elodie Bournique, Ambrocio Sanchez, Sunwoo Oh, Daniel Ghazarian, Alisa L. Mahieu, Lavanya Manjunath, Eirene Ednacot, Pedro Ortega, Selma Masri, Ivan Marazzi, Rémi Buisson

{"title":"ATM and IRAK1 orchestrate two distinct mechanisms of NF-κB activation in response to DNA damage","authors":"Elodie Bournique, Ambrocio Sanchez, Sunwoo Oh, Daniel Ghazarian, Alisa L. Mahieu, Lavanya Manjunath, Eirene Ednacot, Pedro Ortega, Selma Masri, Ivan Marazzi, Rémi Buisson","doi":"10.1038/s41594-024-01417-0","DOIUrl":"https://doi.org/10.1038/s41594-024-01417-0","url":null,"abstract":"DNA damage in cells induces the expression of inflammatory genes. However, the mechanism by which cells initiate an innate immune response in the presence of DNA lesions blocking transcription remains unknown. Here we find that genotoxic stresses lead to an acute activation of the transcription factor NF-κB through two distinct pathways, each triggered by different types of DNA lesions and coordinated by either ataxia-telangiectasia mutated (ATM) or IRAK1 kinases. ATM stimulates NF-κB in cells with DNA double-strand breaks. By contrast, IRAK1-induced NF-κB signaling occurs in neighboring cells through IL-1α secretion from transcriptionally stressed cells caused by DNA lesions blocking RNA polymerases. Subsequently, both pathways stimulate TRAF6 and the IKK complex to promote NF-κB-mediated inflammatory gene expression. These findings provide an alternative mechanism for damaged cells with impaired transcription to initiate an inflammatory response without relying on their own gene expression, a necessary step that injured cells depend on during canonical innate immune responses.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"28 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interfacial water confers transcription factors with dinucleotide specificity

Nature structural & molecular biology Pub Date : 2025-01-03 DOI: 10.1038/s41594-024-01449-6

Ekaterina Morgunova, Gabor Nagy, Yimeng Yin, Fangjie Zhu, Sonali Priyadarshini Nayak, Tianyi Xiao, Ilya Sokolov, Alexander Popov, Charles Laughton, Helmut Grubmuller, Jussi Taipale

{"title":"Interfacial water confers transcription factors with dinucleotide specificity","authors":"Ekaterina Morgunova, Gabor Nagy, Yimeng Yin, Fangjie Zhu, Sonali Priyadarshini Nayak, Tianyi Xiao, Ilya Sokolov, Alexander Popov, Charles Laughton, Helmut Grubmuller, Jussi Taipale","doi":"10.1038/s41594-024-01449-6","DOIUrl":"https://doi.org/10.1038/s41594-024-01449-6","url":null,"abstract":"Transcription factors (TFs) recognize specific bases within their DNA-binding motifs, with each base contributing nearly independently to total binding energy. However, the energetic contributions of particular dinucleotides can deviate strongly from the additive approximation, indicating that some TFs can specifically recognize DNA dinucleotides. Here we solved high-resolution (<1 Å) structures of MYF5 and BARHL2 bound to DNAs containing sets of dinucleotides that have different affinities to the proteins. The dinucleotides were recognized either enthalpically, by an extensive water network that connects the adjacent bases to the TF, or entropically, by a hydrophobic patch that maintained interfacial water mobility. This mechanism confers differential temperature sensitivity to the optimal sites, with implications for thermal regulation of gene expression. Our results uncover the enigma of how TFs can recognize more complex local features than mononucleotides and demonstrate that water-mediated recognition is important for predicting affinities of macromolecules from their sequence.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

KIF1C activates and extends dynein movement through the FHF cargo adapter

Nature structural & molecular biology Pub Date : 2025-01-02 DOI: 10.1038/s41594-024-01418-z

Ferdos Abid Ali, Alexander J. Zwetsloot, Caroline E. Stone, Tomos E. Morgan, Richard F. Wademan, Andrew P. Carter, Anne Straube

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Intronic variant increases Parkinson disease risk by disrupting branchpoint sequence

Nature structural & molecular biology Pub Date : 2025-01-02 DOI: 10.1038/s41594-024-01424-1

引用次数: 0