Nature structural & molecular biology最新文献_第4页

Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth EZH2 和 REST 抑制剂对超级沉默子的扰动会导致染色质相互作用的大量丧失，并降低癌症生长速度

Nature structural & molecular biology Pub Date : 2024-09-20 DOI: 10.1038/s41594-024-01391-7

Ying Zhang, Kaijing Chen, Seng Chuan Tang, Yichao Cai, Akiko Nambu, Yi Xiang See, Chaoyu Fu, Anandhkumar Raju, Benjamin Lebeau, Zixun Ling, Jia Jia Chan, Yvonne Tay, Marek Mutwil, Manikandan Lakshmanan, Greg Tucker-Kellogg, Wee Joo Chng, Daniel G. Tenen, Motomi Osato, Vinay Tergaonkar, Melissa Jane Fullwood

{"title":"Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth","authors":"Ying Zhang, Kaijing Chen, Seng Chuan Tang, Yichao Cai, Akiko Nambu, Yi Xiang See, Chaoyu Fu, Anandhkumar Raju, Benjamin Lebeau, Zixun Ling, Jia Jia Chan, Yvonne Tay, Marek Mutwil, Manikandan Lakshmanan, Greg Tucker-Kellogg, Wee Joo Chng, Daniel G. Tenen, Motomi Osato, Vinay Tergaonkar, Melissa Jane Fullwood","doi":"10.1038/s41594-024-01391-7","DOIUrl":"https://doi.org/10.1038/s41594-024-01391-7","url":null,"abstract":"Human silencers have been shown to regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form ‘super-silencers’ and whether they are linked to cancer progression. Here, we show two silencer components of the FGF18 gene can cooperate through compensatory chromatin interactions to form a super-silencer. Double knockout of two silencers exhibited synergistic upregulation of FGF18 expression and changes in cell identity. To perturb the super-silencers, we applied combinational treatment of an enhancer of zeste homolog 2 inhibitor GSK343, and a repressor element 1-silencing transcription factor inhibitor, X5050 (‘GR’). Interestingly, GR led to severe loss of topologically associated domains and loops, which were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GR synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects in vivo. Overall, our data demonstrated a super-silencer example and showed that GR can disrupt super-silencers, potentially leading to cancer ablation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"215 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276078","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

Catalytic and noncatalytic functions of DNA polymerase κ in translesion DNA synthesis DNA 聚合酶 κ 在转座子 DNA 合成中的催化和非催化功能

Nature structural & molecular biology Pub Date : 2024-09-19 DOI: 10.1038/s41594-024-01395-3

Selene Sellés-Baiget, Sara M. Ambjørn, Alberto Carli, Ivo A. Hendriks, Irene Gallina, Norman E. Davey, Bente Benedict, Alessandra Zarantonello, Sampath A. Gadi, Bob Meeusen, Emil P. T. Hertz, Laura Slappendel, Daniel Semlow, Shana Sturla, Michael L. Nielsen, Jakob Nilsson, Thomas C. R. Miller, Julien P. Duxin

{"title":"Catalytic and noncatalytic functions of DNA polymerase κ in translesion DNA synthesis","authors":"Selene Sellés-Baiget, Sara M. Ambjørn, Alberto Carli, Ivo A. Hendriks, Irene Gallina, Norman E. Davey, Bente Benedict, Alessandra Zarantonello, Sampath A. Gadi, Bob Meeusen, Emil P. T. Hertz, Laura Slappendel, Daniel Semlow, Shana Sturla, Michael L. Nielsen, Jakob Nilsson, Thomas C. R. Miller, Julien P. Duxin","doi":"10.1038/s41594-024-01395-3","DOIUrl":"https://doi.org/10.1038/s41594-024-01395-3","url":null,"abstract":"Translesion DNA synthesis (TLS) is a cellular process that enables the bypass of DNA lesions encountered during DNA replication and is emerging as a primary target of chemotherapy. Among vertebrate DNA polymerases, polymerase κ (Polκ) has the distinctive ability to bypass minor groove DNA adducts in vitro. However, Polκ is also required for cells to overcome major groove DNA adducts but the basis of this requirement is unclear. Here, we combine CRISPR base-editor screening technology in human cells with TLS analysis of defined DNA lesions in Xenopus egg extracts to unravel the functions and regulations of Polκ during lesion bypass. Strikingly, we show that Polκ has two main functions during TLS, which are differentially regulated by Rev1 binding. On the one hand, Polκ is essential to replicate across a minor groove DNA lesion in a process that depends on PCNA ubiquitylation but is independent of Rev1. On the other hand, through its cooperative interaction with Rev1 and ubiquitylated PCNA, Polκ appears to stabilize the Rev1–Polζ extension complex on DNA to allow extension past major groove DNA lesions and abasic sites, in a process that is independent of Polκ’s catalytic activity. Together, our work identifies catalytic and noncatalytic functions of Polκ in TLS and reveals important regulatory mechanisms underlying the unique domain architecture present at the C-terminal end of Y-family TLS polymerases.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245303","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 translational control by the human 48S initiation complex 人类 48S 启动复合体控制翻译的结构基础

Nature structural & molecular biology Pub Date : 2024-09-17 DOI: 10.1038/s41594-024-01378-4

Valentyn Petrychenko, Sung-Hui Yi, David Liedtke, Bee-Zen Peng, Marina V. Rodnina, Niels Fischer

引用次数: 0

Resistance of estrogen receptor function to BET bromodomain inhibition is mediated by transcriptional coactivator cooperativity 雌激素受体功能对 BET 溴链抑制的抗性是由转录协同激活剂的合作性介导的

Nature structural & molecular biology Pub Date : 2024-09-09 DOI: 10.1038/s41594-024-01384-6

Sicong Zhang, Robert G. Roeder

{"title":"Resistance of estrogen receptor function to BET bromodomain inhibition is mediated by transcriptional coactivator cooperativity","authors":"Sicong Zhang, Robert G. Roeder","doi":"10.1038/s41594-024-01384-6","DOIUrl":"https://doi.org/10.1038/s41594-024-01384-6","url":null,"abstract":"The bromodomain and extraterminal domain (BET) family of proteins are critical chromatin readers that bind to acetylated histones through their bromodomains to activate transcription. Here, we reveal that bromodomain inhibition fails to repress oncogenic targets of estrogen receptor because of an intrinsic transcriptional mechanism. While bromodomains are necessary for the transcription of many genes, bromodomain-containing protein 4 (BRD4) binds to estrogen receptor binding sites and activates transcription of critical oncogenes such as MYC, independently of its bromodomains. BRD4 associates with the Mediator complex and disruption of Mediator reduces BRD4’s enhancer occupancy. Profiling changes of the post-initiation RNA polymerase II (Pol II)-associated factors revealed that BET proteins regulate interactions between Pol II and elongation factors SPT5, SPT6 and the polymerase-associated factor 1 complex, which associate with BET proteins independently of their bromodomains and mediate their transcription elongation effect. Our findings highlight the importance of bromodomain-independent functions and interactions of BET proteins in the development of future therapeutic strategies.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158996","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

Pseudouridine guides germline small RNA transport and epigenetic inheritance 伪尿嘧啶引导种系小 RNA 运输和表观遗传

Nature structural & molecular biology Pub Date : 2024-09-06 DOI: 10.1038/s41594-024-01392-6

Rowan P. Herridge, Jakub Dolata, Valentina Migliori, Cristiane de Santis Alves, Filipe Borges, Andrea J. Schorn, Frédéric van Ex, Ann Lin, Mateusz Bajczyk, Jean-Sebastien Parent, Tommaso Leonardi, Alan Hendrick, Tony Kouzarides, Robert A. Martienssen

{"title":"Pseudouridine guides germline small RNA transport and epigenetic inheritance","authors":"Rowan P. Herridge, Jakub Dolata, Valentina Migliori, Cristiane de Santis Alves, Filipe Borges, Andrea J. Schorn, Frédéric van Ex, Ann Lin, Mateusz Bajczyk, Jean-Sebastien Parent, Tommaso Leonardi, Alan Hendrick, Tony Kouzarides, Robert A. Martienssen","doi":"10.1038/s41594-024-01392-6","DOIUrl":"https://doi.org/10.1038/s41594-024-01392-6","url":null,"abstract":"Developmental epigenetic modifications in plants and animals are mostly reset during gamete formation but some are inherited from the germline. Small RNAs guide these epigenetic modifications but how inherited small RNAs are distinguished in plants and animals is unknown. Pseudouridine (Ψ) is the most abundant RNA modification but has not been explored in small RNAs. Here, we develop assays to detect Ψ in short RNA sequences, demonstrating its presence in mouse and Arabidopsis microRNAs. Germline small RNAs, namely epigenetically activated small interfering RNAs (easiRNAs) in Arabidopsis pollen and Piwi-interacting RNAs in mouse testes, are enriched for Ψ. In pollen, pseudouridylated easiRNAs are transported to sperm cells from the vegetative nucleus, and PAUSED/HEN5 (PSD), the plant homolog of Exportin-t, interacts genetically with Ψ and is required for this transport. We further show that Exportin-t is required for the triploid block: small RNA dosage-dependent seed lethality that is epigenetically inherited from pollen. Thus, Ψ has a conserved role in marking inherited small RNAs in the germline.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"380 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142142436","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

Exocyst stimulates multiple steps of exocytic SNARE complex assembly and vesicle fusion 外囊刺激外细胞 SNARE 复合物组装和囊泡融合的多个步骤

Nature structural & molecular biology Pub Date : 2024-09-06 DOI: 10.1038/s41594-024-01388-2

Chanwoo Lee, Dante Lepore, Seung-Hak Lee, Tae Gyun Kim, Natasha Buwa, Jongchan Lee, Mary Munson, Tae-Young Yoon

{"title":"Exocyst stimulates multiple steps of exocytic SNARE complex assembly and vesicle fusion","authors":"Chanwoo Lee, Dante Lepore, Seung-Hak Lee, Tae Gyun Kim, Natasha Buwa, Jongchan Lee, Mary Munson, Tae-Young Yoon","doi":"10.1038/s41594-024-01388-2","DOIUrl":"https://doi.org/10.1038/s41594-024-01388-2","url":null,"abstract":"Exocyst is a large multisubunit tethering complex essential for targeting and fusion of secretory vesicles in eukaryotic cells. Although the assembled exocyst complex has been proposed to tether vesicles to the plasma membrane and activate soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) for membrane fusion, the key biochemical steps that exocyst stimulates in SNARE-mediated fusion are undetermined. Here we use a combination of single-molecule and bulk fluorescence assays to investigate the roles of purified octameric yeast exocyst complexes in a reconstituted yeast exocytic SNARE assembly and vesicle fusion system. Exocyst had stimulatory roles in multiple distinct steps ranging from SNARE protein activation to binary and ternary complex assembly. Importantly, exocyst had a downstream role in driving membrane fusion and full content mixing of vesicle lumens. Our data suggest that exocyst provides extensive chaperoning functions across the entire process of SNARE complex assembly and fusion, thereby governing exocytosis at multiple steps.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142142420","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

Distinct stabilization of the human T cell leukemia virus type 1 immature Gag lattice 人类 T 细胞白血病病毒 1 型未成熟 Gag 网格的独特稳定性

Nature structural & molecular biology Pub Date : 2024-09-06 DOI: 10.1038/s41594-024-01390-8

Martin Obr, Mathias Percipalle, Darya Chernikova, Huixin Yang, Andreas Thader, Gergely Pinke, Dario Porley, Louis M. Mansky, Robert A. Dick, Florian K. M. Schur

引用次数: 0

Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis 抗 NMDAR 自身免疫性脑炎的结构和功能机制

Nature structural & molecular biology Pub Date : 2024-09-03 DOI: 10.1038/s41594-024-01386-4

Kevin Michalski, Taha Abdulla, Sam Kleeman, Lars Schmidl, Ricardo Gómez, Noriko Simorowski, Francesca Vallese, Harald Prüss, Manfred Heckmann, Christian Geis, Hiro Furukawa

{"title":"Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis","authors":"Kevin Michalski, Taha Abdulla, Sam Kleeman, Lars Schmidl, Ricardo Gómez, Noriko Simorowski, Francesca Vallese, Harald Prüss, Manfred Heckmann, Christian Geis, Hiro Furukawa","doi":"10.1038/s41594-024-01386-4","DOIUrl":"https://doi.org/10.1038/s41594-024-01386-4","url":null,"abstract":"Autoantibodies against neuronal membrane proteins can manifest in autoimmune encephalitis, inducing seizures, cognitive dysfunction and psychosis. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most dominant autoimmune encephalitis; however, insights into how autoantibodies recognize and alter receptor functions remain limited. Here we determined structures of human and rat NMDARs bound to three distinct patient-derived antibodies using single-particle electron cryo-microscopy. These antibodies bind different regions within the amino-terminal domain of the GluN1 subunit. Through electrophysiology, we show that all three autoantibodies acutely and directly reduced NMDAR channel functions in primary neurons. Antibodies show different stoichiometry of binding and antibody–receptor complex formation, which in one antibody, 003-102, also results in reduced synaptic localization of NMDARs. These studies demonstrate mechanisms of diverse epitope recognition and direct channel regulation of anti-NMDAR autoantibodies underlying autoimmune encephalitis.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123517","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 antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis 自身免疫性脑炎中抗体介导的 NMDA 受体聚集和内吞的结构基础

Nature structural & molecular biology Pub Date : 2024-09-03 DOI: 10.1038/s41594-024-01387-3

Han Wang, Chun Xie, Bo Deng, Jingjun Ding, Na Li, Zengwei Kou, Mengmeng Jin, Jie He, Qinrui Wang, Han Wen, Jinbao Zhang, Qinming Zhou, Sheng Chen, Xiangjun Chen, Ti-Fei Yuan, Shujia Zhu

{"title":"Structural basis for antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis","authors":"Han Wang, Chun Xie, Bo Deng, Jingjun Ding, Na Li, Zengwei Kou, Mengmeng Jin, Jie He, Qinrui Wang, Han Wen, Jinbao Zhang, Qinming Zhou, Sheng Chen, Xiangjun Chen, Ti-Fei Yuan, Shujia Zhu","doi":"10.1038/s41594-024-01387-3","DOIUrl":"https://doi.org/10.1038/s41594-024-01387-3","url":null,"abstract":"Antibodies against N-methyl-d-aspartate receptors (NMDARs) are most frequently detected in persons with autoimmune encephalitis (AE) and used as diagnostic biomarkers. Elucidating the structural basis of monoclonal antibody (mAb) binding to NMDARs would facilitate the development of targeted therapy for AE. Here, we reconstructed nanodiscs containing green fluorescent protein-fused NMDARs to label and sort individual immune B cells from persons with AE and further cloned and identified mAbs against NMDARs. This allowed cryo-electron microscopy analysis of NMDAR–Fab complexes, revealing that autoantibodies bind to the R1 lobe of the N-terminal domain of the GluN1 subunit. Small-angle X-ray scattering studies demonstrated NMDAR–mAb stoichiometry of 2:1 or 1:2, structurally suitable for mAb-induced clustering and endocytosis of NMDARs. Importantly, these mAbs reduced the surface NMDARs and NMDAR-mediated currents, without tonically affecting NMDAR channel gating. These structural and functional findings imply that the design of neutralizing antibody binding to the R1 lobe of NMDARs represents a potential therapy for AE treatment.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"102 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123520","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

Shieldin and CST co-orchestrate DNA polymerase-dependent tailed-end joining reactions independently of 53BP1-governed repair pathway choice Shieldin 和 CST 共同协调 DNA 聚合酶依赖性尾端连接反应，与 53BP1 主导的修复途径选择无关

Nature structural & molecular biology Pub Date : 2024-09-03 DOI: 10.1038/s41594-024-01381-9

Ashleigh King, Pia I. Reichl, Jean S. Metson, Robert Parker, Daniella Munro, Catarina Oliveira, Lucia Sommerova, Jordan R. Becker, Daniel Biggs, Chris Preece, Benjamin Davies, J. Ross Chapman

{"title":"Shieldin and CST co-orchestrate DNA polymerase-dependent tailed-end joining reactions independently of 53BP1-governed repair pathway choice","authors":"Ashleigh King, Pia I. Reichl, Jean S. Metson, Robert Parker, Daniella Munro, Catarina Oliveira, Lucia Sommerova, Jordan R. Becker, Daniel Biggs, Chris Preece, Benjamin Davies, J. Ross Chapman","doi":"10.1038/s41594-024-01381-9","DOIUrl":"https://doi.org/10.1038/s41594-024-01381-9","url":null,"abstract":"Tumor suppressor p53-binding protein 1 (53BP1) regulates DNA end joining in lymphocytes, diversifying immune antigen receptors. This involves nucleosome-bound 53BP1 at DNA double-stranded breaks (DSBs) recruiting Rap1-interacting factor 1 homolog (RIF1) and shieldin, a poorly understood DNA-binding complex. The 53BP1–RIF1–shieldin axis is pathological in BRCA1-mutated cancers, blocking homologous recombination (HR) and driving illegitimate nonhomologous end joining (NHEJ). However, how this axis regulates DNA end joining and HR suppression remains unresolved. We investigated shieldin and its interplay with the Ctc1–Stn1–Ten1 (CST) complex, which was recently implicated downstream of 53BP1. Immunophenotypically, mice lacking shieldin or CST are equivalent, with class-switch recombination coreliant on both complexes. Ataxia-telangiectasia mutated kinase-dependent DNA damage signaling underpins this cooperation, inducing physical interactions between these complexes that reveal shieldin as a DSB-responsive CST adaptor. Furthermore, DNA polymerase ζ functions downstream of shieldin, establishing DNA fill-in synthesis as the physiological function of shieldin–CST. Lastly, we demonstrate that 53BP1 suppresses HR and promotes NHEJ in BRCA1-deficient mice and cells independently of shieldin. These findings showcase the versatility of the 53BP1 pathway, achieved through the collaboration of chromatin-bound 53BP1 complexes and DNA end-processing effector proteins.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123592","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