Pub Date : 2024-05-30DOI: 10.1038/s41594-024-01324-4
Eva Nogales
Macromolecules are involved in myriads of interactions that regulate their cellular function. While years of structural biology progress was built by reducing this complexity, a molecular understanding of biological processes requires the characterization of ever larger and more dynamic molecular assemblies. Cryo-electron microscopy is rising to this challenge.
{"title":"Building up complexity in structural biology studies","authors":"Eva Nogales","doi":"10.1038/s41594-024-01324-4","DOIUrl":"10.1038/s41594-024-01324-4","url":null,"abstract":"Macromolecules are involved in myriads of interactions that regulate their cellular function. While years of structural biology progress was built by reducing this complexity, a molecular understanding of biological processes requires the characterization of ever larger and more dynamic molecular assemblies. Cryo-electron microscopy is rising to this challenge.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 6","pages":"847-848"},"PeriodicalIF":16.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177504","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 : 2024-05-29DOI: 10.1038/s41594-024-01296-5
Ramanujan S. Hegde, Robert J. Keenan
α-Helical integral membrane proteins comprise approximately 25% of the proteome in all organisms. The membrane proteome is highly diverse, varying in the number, topology, spacing and properties of transmembrane domains. This diversity imposes different constraints on the insertion of different regions of a membrane protein into the lipid bilayer. Here, we present a cohesive framework to explain membrane protein biogenesis, in which different parts of a nascent substrate are triaged between Oxa1 and SecY family members for insertion. In this model, Oxa1 family proteins insert transmembrane domains flanked by short translocated segments, whereas the SecY channel is required for insertion of transmembrane domains flanked by long translocated segments. Our unifying model rationalizes evolutionary, genetic, biochemical and structural data across organisms and provides a foundation for future mechanistic studies of membrane protein biogenesis. In this Perspective, the authors propose a framework to explain membrane protein biogenesis, wherein different parts of a nascent substrate are triaged between Oxa1 and SecY family members for insertion.
{"title":"A unifying model for membrane protein biogenesis","authors":"Ramanujan S. Hegde, Robert J. Keenan","doi":"10.1038/s41594-024-01296-5","DOIUrl":"10.1038/s41594-024-01296-5","url":null,"abstract":"α-Helical integral membrane proteins comprise approximately 25% of the proteome in all organisms. The membrane proteome is highly diverse, varying in the number, topology, spacing and properties of transmembrane domains. This diversity imposes different constraints on the insertion of different regions of a membrane protein into the lipid bilayer. Here, we present a cohesive framework to explain membrane protein biogenesis, in which different parts of a nascent substrate are triaged between Oxa1 and SecY family members for insertion. In this model, Oxa1 family proteins insert transmembrane domains flanked by short translocated segments, whereas the SecY channel is required for insertion of transmembrane domains flanked by long translocated segments. Our unifying model rationalizes evolutionary, genetic, biochemical and structural data across organisms and provides a foundation for future mechanistic studies of membrane protein biogenesis. In this Perspective, the authors propose a framework to explain membrane protein biogenesis, wherein different parts of a nascent substrate are triaged between Oxa1 and SecY family members for insertion.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 7","pages":"1009-1017"},"PeriodicalIF":12.5,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165362","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 : 2024-05-29DOI: 10.1038/s41594-024-01322-6
Junjiao Yang, Chan-I Chung, Jessica Koach, Hongjiang Liu, Ambuja Navalkar, Hao He, Zhimin Ma, Qian Zhao, Xiaoyu Yang, Liang He, Tanja Mittag, Yin Shen, William A. Weiss, Xiaokun Shu
Dysregulation and enhanced expression of MYC transcription factors (TFs) including MYC and MYCN contribute to the majority of human cancers. For example, MYCN is amplified up to several hundredfold in high-risk neuroblastoma. The resulting overexpression of N-myc aberrantly activates genes that are not activated at low N-myc levels and drives cell proliferation. Whether increasing N-myc levels simply mediates binding to lower-affinity binding sites in the genome or fundamentally changes the activation process remains unclear. One such activation mechanism that could become important above threshold levels of N-myc is the formation of aberrant transcriptional condensates through phase separation. Phase separation has recently been linked to transcriptional regulation, but the extent to which it contributes to gene activation remains an open question. Here we characterized the phase behavior of N-myc and showed that it can form dynamic condensates that have transcriptional hallmarks. We tested the role of phase separation in N-myc-regulated transcription by using a chemogenetic tool that allowed us to compare non-phase-separated and phase-separated conditions at equivalent N-myc levels, both of which showed a strong impact on gene expression compared to no N-myc expression. Interestingly, we discovered that only a small percentage (<3%) of N-myc-regulated genes is further modulated by phase separation but that these events include the activation of key oncogenes and the repression of tumor suppressors. Indeed, phase separation increases cell proliferation, corroborating the biological effects of the transcriptional changes. However, our results also show that >97% of N-myc-regulated genes are not affected by N-myc phase separation, demonstrating that soluble complexes of TFs with the transcriptional machinery are sufficient to activate transcription. Oncoprotein transcription factor MYC undergoes phase separation, forming transcriptionally active condensates. The chemogenetic tool SPARK-ON reveals that MYC phase separation selectively modulates the transcriptome and promotes cell proliferation.
{"title":"MYC phase separation selectively modulates the transcriptome","authors":"Junjiao Yang, Chan-I Chung, Jessica Koach, Hongjiang Liu, Ambuja Navalkar, Hao He, Zhimin Ma, Qian Zhao, Xiaoyu Yang, Liang He, Tanja Mittag, Yin Shen, William A. Weiss, Xiaokun Shu","doi":"10.1038/s41594-024-01322-6","DOIUrl":"10.1038/s41594-024-01322-6","url":null,"abstract":"Dysregulation and enhanced expression of MYC transcription factors (TFs) including MYC and MYCN contribute to the majority of human cancers. For example, MYCN is amplified up to several hundredfold in high-risk neuroblastoma. The resulting overexpression of N-myc aberrantly activates genes that are not activated at low N-myc levels and drives cell proliferation. Whether increasing N-myc levels simply mediates binding to lower-affinity binding sites in the genome or fundamentally changes the activation process remains unclear. One such activation mechanism that could become important above threshold levels of N-myc is the formation of aberrant transcriptional condensates through phase separation. Phase separation has recently been linked to transcriptional regulation, but the extent to which it contributes to gene activation remains an open question. Here we characterized the phase behavior of N-myc and showed that it can form dynamic condensates that have transcriptional hallmarks. We tested the role of phase separation in N-myc-regulated transcription by using a chemogenetic tool that allowed us to compare non-phase-separated and phase-separated conditions at equivalent N-myc levels, both of which showed a strong impact on gene expression compared to no N-myc expression. Interestingly, we discovered that only a small percentage (<3%) of N-myc-regulated genes is further modulated by phase separation but that these events include the activation of key oncogenes and the repression of tumor suppressors. Indeed, phase separation increases cell proliferation, corroborating the biological effects of the transcriptional changes. However, our results also show that >97% of N-myc-regulated genes are not affected by N-myc phase separation, demonstrating that soluble complexes of TFs with the transcriptional machinery are sufficient to activate transcription. Oncoprotein transcription factor MYC undergoes phase separation, forming transcriptionally active condensates. The chemogenetic tool SPARK-ON reveals that MYC phase separation selectively modulates the transcriptome and promotes cell proliferation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1567-1579"},"PeriodicalIF":12.5,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01322-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165114","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 : 2024-05-28DOI: 10.1038/s41594-024-01323-5
Jochen Kuper, Tamsanqa Hove, Sarah Maidl, Hermann Neitz, Florian Sauer, Maximilian Kempf, Till Schroeder, Elke Greiter, Claudia Höbartner, Caroline Kisker
The superfamily 2 helicase XPD is a central component of the general transcription factor II H (TFIIH), which is essential for transcription and nucleotide excision DNA repair (NER). Within these two processes, the helicase function of XPD is vital for NER but not for transcription initiation, where XPD acts only as a scaffold for other factors. Using cryo-EM, we deciphered one of the most enigmatic steps in XPD helicase action: the active separation of double-stranded DNA (dsDNA) and its stalling upon approaching a DNA interstrand cross-link, a highly toxic form of DNA damage. The structure shows how dsDNA is separated and reveals a highly unusual involvement of the Arch domain in active dsDNA separation. Combined with mutagenesis and biochemical analyses, we identified distinct functional regions important for helicase activity. Surprisingly, those areas also affect core TFIIH translocase activity, revealing a yet unencountered function of XPD within the TFIIH scaffold. In summary, our data provide a universal basis for NER bubble formation, XPD damage verification and XPG incision. Here, using cryo-EM and biochemistry, the authors delineate how the XPD helicase unorthodoxly uses its Arch domain to separate double-stranded DNA upon approaching a DNA lesion, promoting our understanding of NER bubble formation and damage verification.
超家族 2 螺旋酶 XPD 是一般转录因子 II H（TFIIH）的核心成分，它对转录和核苷酸切割 DNA 修复（NER）至关重要。在这两个过程中，XPD 的螺旋酶功能对 NER 至关重要，但对转录起始并不重要，在转录起始过程中，XPD 只充当其他因子的支架。我们利用低温电子显微镜破译了 XPD 螺旋酶作用中最神秘的步骤之一：主动分离双链 DNA（dsDNA），并在接近 DNA 链间交联（一种剧毒的 DNA 损伤形式）时停滞。该结构显示了dsDNA是如何分离的，并揭示了Arch结构域在主动分离dsDNA过程中极不寻常的参与。结合诱变和生化分析，我们确定了对螺旋酶活性非常重要的不同功能区。令人惊讶的是，这些区域也影响了 TFIIH 核心转位酶的活性，揭示了 XPD 在 TFIIH 支架中尚未遇到的功能。总之，我们的数据为 NER 气泡形成、XPD 损伤验证和 XPG 切割提供了一个普遍基础。
{"title":"XPD stalled on cross-linked DNA provides insight into damage verification","authors":"Jochen Kuper, Tamsanqa Hove, Sarah Maidl, Hermann Neitz, Florian Sauer, Maximilian Kempf, Till Schroeder, Elke Greiter, Claudia Höbartner, Caroline Kisker","doi":"10.1038/s41594-024-01323-5","DOIUrl":"10.1038/s41594-024-01323-5","url":null,"abstract":"The superfamily 2 helicase XPD is a central component of the general transcription factor II H (TFIIH), which is essential for transcription and nucleotide excision DNA repair (NER). Within these two processes, the helicase function of XPD is vital for NER but not for transcription initiation, where XPD acts only as a scaffold for other factors. Using cryo-EM, we deciphered one of the most enigmatic steps in XPD helicase action: the active separation of double-stranded DNA (dsDNA) and its stalling upon approaching a DNA interstrand cross-link, a highly toxic form of DNA damage. The structure shows how dsDNA is separated and reveals a highly unusual involvement of the Arch domain in active dsDNA separation. Combined with mutagenesis and biochemical analyses, we identified distinct functional regions important for helicase activity. Surprisingly, those areas also affect core TFIIH translocase activity, revealing a yet unencountered function of XPD within the TFIIH scaffold. In summary, our data provide a universal basis for NER bubble formation, XPD damage verification and XPG incision. Here, using cryo-EM and biochemistry, the authors delineate how the XPD helicase unorthodoxly uses its Arch domain to separate double-stranded DNA upon approaching a DNA lesion, promoting our understanding of NER bubble formation and damage verification.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1580-1588"},"PeriodicalIF":12.5,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01323-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159521","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 : 2024-05-24DOI: 10.1038/s41594-024-01314-6
Yingxia Hu, Krista A. Delviks-Frankenberry, Chunxiang Wu, Fidel Arizaga, Vinay K. Pathak, Yong Xiong
HIV-1 Vif recruits host cullin-RING-E3 ubiquitin ligase and CBFβ to degrade the cellular APOBEC3 antiviral proteins through diverse interactions. Recent evidence has shown that Vif also degrades the regulatory subunits PPP2R5(A–E) of cellular protein phosphatase 2A to induce G2/M cell cycle arrest. As PPP2R5 proteins bear no functional or structural resemblance to A3s, it is unclear how Vif can recognize different sets of proteins. Here we report the cryogenic-electron microscopy structure of PPP2R5A in complex with HIV-1 Vif–CBFβ–elongin B–elongin C at 3.58 Å resolution. The structure shows PPP2R5A binds across the Vif molecule, with biochemical and cellular studies confirming a distinct Vif–PPP2R5A interface that partially overlaps with those for A3s. Vif also blocks a canonical PPP2R5A substrate-binding site, indicating that it suppresses the phosphatase activities through both degradation-dependent and degradation-independent mechanisms. Our work identifies critical Vif motifs regulating the recognition of diverse A3 and PPP2R5A substrates, whereby disruption of these host–virus protein interactions could serve as potential targets for HIV-1 therapeutics. The authors solve a cryo-EM structure of the regulatory subunit of human protein phosphatase 2A in complex with HIV-1 Vif-containing E3 ligase, leading to improvement of our understanding of host–virus protein interactions.
{"title":"Structural insights into PPP2R5A degradation by HIV-1 Vif","authors":"Yingxia Hu, Krista A. Delviks-Frankenberry, Chunxiang Wu, Fidel Arizaga, Vinay K. Pathak, Yong Xiong","doi":"10.1038/s41594-024-01314-6","DOIUrl":"10.1038/s41594-024-01314-6","url":null,"abstract":"HIV-1 Vif recruits host cullin-RING-E3 ubiquitin ligase and CBFβ to degrade the cellular APOBEC3 antiviral proteins through diverse interactions. Recent evidence has shown that Vif also degrades the regulatory subunits PPP2R5(A–E) of cellular protein phosphatase 2A to induce G2/M cell cycle arrest. As PPP2R5 proteins bear no functional or structural resemblance to A3s, it is unclear how Vif can recognize different sets of proteins. Here we report the cryogenic-electron microscopy structure of PPP2R5A in complex with HIV-1 Vif–CBFβ–elongin B–elongin C at 3.58 Å resolution. The structure shows PPP2R5A binds across the Vif molecule, with biochemical and cellular studies confirming a distinct Vif–PPP2R5A interface that partially overlaps with those for A3s. Vif also blocks a canonical PPP2R5A substrate-binding site, indicating that it suppresses the phosphatase activities through both degradation-dependent and degradation-independent mechanisms. Our work identifies critical Vif motifs regulating the recognition of diverse A3 and PPP2R5A substrates, whereby disruption of these host–virus protein interactions could serve as potential targets for HIV-1 therapeutics. The authors solve a cryo-EM structure of the regulatory subunit of human protein phosphatase 2A in complex with HIV-1 Vif-containing E3 ligase, leading to improvement of our understanding of host–virus protein interactions.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1492-1501"},"PeriodicalIF":12.5,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092183","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 : 2024-05-24DOI: 10.1038/s41594-024-01311-9
Meng Zhu, Maciej Meglicki, Adiyant Lamba, Peizhe Wang, Christophe Royer, Karen Turner, Muhammad Abdullah Jauhar, Celine Jones, Tim Child, Kevin Coward, Jie Na, Magdalena Zernicka-Goetz
The mouse and human embryo gradually loses totipotency before diversifying into the inner cell mass (ICM, future organism) and trophectoderm (TE, future placenta). The transcription factors TFAP2C and TEAD4 with activated RHOA accelerate embryo polarization. Here we show that these factors also accelerate the loss of totipotency. TFAP2C and TEAD4 paradoxically promote and inhibit Hippo signaling before lineage diversification: they drive expression of multiple Hippo regulators while also promoting apical domain formation, which inactivates Hippo. Each factor activates TE specifiers in bipotent cells, while TFAP2C also activates specifiers of the ICM fate. Asymmetric segregation of the apical domain reconciles the opposing regulation of Hippo signaling into Hippo OFF and the TE fate, or Hippo ON and the ICM fate. We propose that the bistable switch established by TFAP2C and TEAD4 is exploited to trigger robust lineage diversification in the developing embryo. Here the authors identify the transcription factors TFAP2C and TEAD4 as a bistable switch that reconciles into Hippo ON and OFF states, establishing a composite state at the eight-cell stage and critically regulating lineage diversification.
{"title":"Tead4 and Tfap2c generate bipotency and a bistable switch in totipotent embryos to promote robust lineage diversification","authors":"Meng Zhu, Maciej Meglicki, Adiyant Lamba, Peizhe Wang, Christophe Royer, Karen Turner, Muhammad Abdullah Jauhar, Celine Jones, Tim Child, Kevin Coward, Jie Na, Magdalena Zernicka-Goetz","doi":"10.1038/s41594-024-01311-9","DOIUrl":"10.1038/s41594-024-01311-9","url":null,"abstract":"The mouse and human embryo gradually loses totipotency before diversifying into the inner cell mass (ICM, future organism) and trophectoderm (TE, future placenta). The transcription factors TFAP2C and TEAD4 with activated RHOA accelerate embryo polarization. Here we show that these factors also accelerate the loss of totipotency. TFAP2C and TEAD4 paradoxically promote and inhibit Hippo signaling before lineage diversification: they drive expression of multiple Hippo regulators while also promoting apical domain formation, which inactivates Hippo. Each factor activates TE specifiers in bipotent cells, while TFAP2C also activates specifiers of the ICM fate. Asymmetric segregation of the apical domain reconciles the opposing regulation of Hippo signaling into Hippo OFF and the TE fate, or Hippo ON and the ICM fate. We propose that the bistable switch established by TFAP2C and TEAD4 is exploited to trigger robust lineage diversification in the developing embryo. Here the authors identify the transcription factors TFAP2C and TEAD4 as a bistable switch that reconciles into Hippo ON and OFF states, establishing a composite state at the eight-cell stage and critically regulating lineage diversification.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 6","pages":"964-976"},"PeriodicalIF":16.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01311-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092133","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 : 2024-05-24DOI: 10.1038/s41594-024-01304-8
Chad S. Driscoll, Jaehwan Kim, Jason G. Knott
The molecular mechanisms that regulate the transition from totipotency into divergent cellular states are unclear. Two new studies show that the transcription factors TFAP2C, NR5A2 and TEAD4 (TNT) support the formation of a transient bipotent state by activating early pluripotency and trophectoderm genes and modulating HIPPO signaling.
{"title":"The explosive discovery of TNT in early mouse embryos","authors":"Chad S. Driscoll, Jaehwan Kim, Jason G. Knott","doi":"10.1038/s41594-024-01304-8","DOIUrl":"10.1038/s41594-024-01304-8","url":null,"abstract":"The molecular mechanisms that regulate the transition from totipotency into divergent cellular states are unclear. Two new studies show that the transcription factors TFAP2C, NR5A2 and TEAD4 (TNT) support the formation of a transient bipotent state by activating early pluripotency and trophectoderm genes and modulating HIPPO signaling.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 6","pages":"852-855"},"PeriodicalIF":16.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092176","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 : 2024-05-23DOI: 10.1038/s41594-024-01326-2
Natalya Leneva, Oleksiy Kovtun
The commander complex was recently shown through interactomic screens to be a ubiquitous and conserved protein complex with fundamental biological roles. Two recent reports together revealed the structure of the complete commander assembly and explored its functional implications.
{"title":"The commander complex is the Swiss Army knife of endosomal trafficking","authors":"Natalya Leneva, Oleksiy Kovtun","doi":"10.1038/s41594-024-01326-2","DOIUrl":"10.1038/s41594-024-01326-2","url":null,"abstract":"The commander complex was recently shown through interactomic screens to be a ubiquitous and conserved protein complex with fundamental biological roles. Two recent reports together revealed the structure of the complete commander assembly and explored its functional implications.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 6","pages":"856-858"},"PeriodicalIF":16.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085413","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 : 2024-05-23DOI: 10.1038/s41594-024-01313-7
Maximilian Stötzel, Chieh-Yu Cheng, Ibrahim A. IIik, Abhishek Sampath Kumar, Persia Akbari Omgba, Vera A. van der Weijden, Yufei Zhang, Martin Vingron, Alexander Meissner, Tuğçe Aktaş, Helene Kretzmer, Aydan Bulut-Karslioğlu
Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus in a dormant state called diapause, which can be induced in vitro through mTOR inhibition. Cellular strategies that safeguard original cell identity within the silent genomic landscape of dormancy are not known. Here we show that the protection of cis-regulatory elements from silencing is key to maintaining pluripotency in the dormant state. We reveal a TET–transcription factor axis, in which TET-mediated DNA demethylation and recruitment of methylation-sensitive transcription factor TFE3 drive transcriptionally inert chromatin adaptations during dormancy transition. Perturbation of TET activity compromises pluripotency and survival of mouse embryos under dormancy, whereas its enhancement improves survival rates. Our results reveal an essential mechanism for propagating the cellular identity of dormant cells, with implications for regeneration and disease. Here the authors show that active DNA demethylation and transcription factor occupation at distal regulatory elements is essential for pluripotency maintenance in dormancy conditions.
{"title":"TET activity safeguards pluripotency throughout embryonic dormancy","authors":"Maximilian Stötzel, Chieh-Yu Cheng, Ibrahim A. IIik, Abhishek Sampath Kumar, Persia Akbari Omgba, Vera A. van der Weijden, Yufei Zhang, Martin Vingron, Alexander Meissner, Tuğçe Aktaş, Helene Kretzmer, Aydan Bulut-Karslioğlu","doi":"10.1038/s41594-024-01313-7","DOIUrl":"10.1038/s41594-024-01313-7","url":null,"abstract":"Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus in a dormant state called diapause, which can be induced in vitro through mTOR inhibition. Cellular strategies that safeguard original cell identity within the silent genomic landscape of dormancy are not known. Here we show that the protection of cis-regulatory elements from silencing is key to maintaining pluripotency in the dormant state. We reveal a TET–transcription factor axis, in which TET-mediated DNA demethylation and recruitment of methylation-sensitive transcription factor TFE3 drive transcriptionally inert chromatin adaptations during dormancy transition. Perturbation of TET activity compromises pluripotency and survival of mouse embryos under dormancy, whereas its enhancement improves survival rates. Our results reveal an essential mechanism for propagating the cellular identity of dormant cells, with implications for regeneration and disease. Here the authors show that active DNA demethylation and transcription factor occupation at distal regulatory elements is essential for pluripotency maintenance in dormancy conditions.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1625-1639"},"PeriodicalIF":12.5,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01313-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085341","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 : 2024-05-21DOI: 10.1038/s41594-024-01321-7
Yuichi Shichino, Tomokazu Yamaguchi, Kazuhiro Kashiwagi, Mari Mito, Mari Takahashi, Takuhiro Ito, Nicholas T. Ingolia, Keiji Kuba, Shintaro Iwasaki
Eukaryotic translation initiation factor (eIF)4A—a DEAD-box RNA-binding protein—plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs, whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the interaction between TOP mRNAs and LARP1 and, thus, ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator. The authors revealed that the general translation factor eIF4A exerts a repressive effect on a subset of mRNAs by enhancing LARP1 and TOP mRNAs during mTORC1 inhibition under stress.
{"title":"eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition","authors":"Yuichi Shichino, Tomokazu Yamaguchi, Kazuhiro Kashiwagi, Mari Mito, Mari Takahashi, Takuhiro Ito, Nicholas T. Ingolia, Keiji Kuba, Shintaro Iwasaki","doi":"10.1038/s41594-024-01321-7","DOIUrl":"10.1038/s41594-024-01321-7","url":null,"abstract":"Eukaryotic translation initiation factor (eIF)4A—a DEAD-box RNA-binding protein—plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs, whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the interaction between TOP mRNAs and LARP1 and, thus, ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator. The authors revealed that the general translation factor eIF4A exerts a repressive effect on a subset of mRNAs by enhancing LARP1 and TOP mRNAs during mTORC1 inhibition under stress.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 10","pages":"1557-1566"},"PeriodicalIF":12.5,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074146","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：