Molecular Cell最新文献_第10页

Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle 跨亚细胞区室的全基因组 RNA 流量化揭示了哺乳动物转录本生命周期的决定因素

IF 16 1区生物学

Molecular Cell Pub Date : 2024-07-03 DOI: 10.1016/j.molcel.2024.06.008

Robert Ietswaart, Brendan M. Smalec, Albert Xu, Karine Choquet, Erik McShane, Ziad Mohamoud Jowhar, Chantal K. Guegler, Autum R. Baxter-Koenigs, Emma R. West, Becky Xu Hua Fu, Luke Gilbert, Stephen N. Floor, L. Stirling Churchman

{"title":"Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle","authors":"Robert Ietswaart, Brendan M. Smalec, Albert Xu, Karine Choquet, Erik McShane, Ziad Mohamoud Jowhar, Chantal K. Guegler, Autum R. Baxter-Koenigs, Emma R. West, Becky Xu Hua Fu, Luke Gilbert, Stephen N. Floor, L. Stirling Churchman","doi":"10.1016/j.molcel.2024.06.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.06.008","url":null,"abstract":"Dissecting the regulatory mechanisms controlling mammalian transcripts from production to degradation requires quantitative measurements of mRNA flow across the cell. We developed subcellular TimeLapse-seq to measure the rates at which RNAs are released from chromatin, exported from the nucleus, loaded onto polysomes, and degraded within the nucleus and cytoplasm in human and mouse cells. These rates varied substantially, yet transcripts from genes with related functions or targeted by the same transcription factors and RNA-binding proteins flowed across subcellular compartments with similar kinetics. Verifying these associations uncovered a link between DDX3X and nuclear export. For hundreds of RNA metabolism genes, most transcripts with retained introns were degraded by the nuclear exosome, while the remaining molecules were exported with stable cytoplasmic lifespans. Transcripts residing on chromatin for longer had extended poly(A) tails, whereas the reverse was observed for cytoplasmic mRNAs. Finally, machine learning identified molecular features that predicted the diverse life cycles of mRNAs.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141495897","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}

引用次数: 0

CCAR1 promotes DNA repair via alternative splicing CCAR1 通过替代剪接促进 DNA 修复

IF 16 1区生物学

Molecular Cell Pub Date : 2024-07-03 DOI: 10.1016/j.molcel.2024.06.011

Mehmet E. Karasu, Leonard Jahnke, Brian J. Joseph, Yerkezhan Amerzhanova, Aleksei Mironov, Xuan Shu, Markus S. Schröder, Ana Gvozdenovic, Irene Sala, Mihaela Zavolan, Stefanie Jonas, Jacob E. Corn

引用次数: 0

Cas12a domain flexibility guides R-loop formation and forces RuvC resetting Cas12a 结构域的灵活性引导 R 环的形成，并迫使 RuvC 复位

IF 16 1区生物学

Molecular Cell Pub Date : 2024-07-01 DOI: 10.1016/j.molcel.2024.06.007

Isabel Strohkendl, Aakash Saha, Catherine Moy, Alexander-Hoi Nguyen, Mohd Ahsan, Rick Russell, Giulia Palermo, David W. Taylor

{"title":"Cas12a domain flexibility guides R-loop formation and forces RuvC resetting","authors":"Isabel Strohkendl, Aakash Saha, Catherine Moy, Alexander-Hoi Nguyen, Mohd Ahsan, Rick Russell, Giulia Palermo, David W. Taylor","doi":"10.1016/j.molcel.2024.06.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.06.007","url":null,"abstract":"The specific nature of CRISPR-Cas12a makes it a desirable RNA-guided endonuclease for biotechnology and therapeutic applications. To understand how R-loop formation within the compact Cas12a enables target recognition and nuclease activation, we used cryo-electron microscopy to capture wild-type Acidaminococcus sp. Cas12a R-loop intermediates and DNA delivery into the RuvC active site. Stages of Cas12a R-loop formation—starting from a 5-bp seed—are marked by distinct REC domain arrangements. Dramatic domain flexibility limits contacts until nearly complete R-loop formation, when the non-target strand is pulled across the RuvC nuclease and coordinated domain docking promotes efficient cleavage. Next, substantial domain movements enable target strand repositioning into the RuvC active site. Between cleavage events, the RuvC lid conformationally resets to occlude the active site, requiring re-activation. These snapshots build a structural model depicting Cas12a DNA targeting that rationalizes observed specificity and highlights mechanistic comparisons to other class 2 effectors.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489721","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}

引用次数: 0

An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II 核受体控制 Mediator 与 RNA 聚合酶 II 交互作用的 IDR 依赖性机制

IF 16 1区生物学

Molecular Cell Pub Date : 2024-07-01 DOI: 10.1016/j.molcel.2024.06.006

Haiyan Zhao, Jiaqin Li, Yufei Xiang, Sohail Malik, Supriya V. Vartak, Giovana M.B. Veronezi, Natalie Young, McKayla Riney, Jens Kalchschmidt, Andrea Conte, Seol Kyoung Jung, Srinivas Ramachandran, Robert G. Roeder, Yi Shi, Rafael Casellas, Francisco J. Asturias

{"title":"An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II","authors":"Haiyan Zhao, Jiaqin Li, Yufei Xiang, Sohail Malik, Supriya V. Vartak, Giovana M.B. Veronezi, Natalie Young, McKayla Riney, Jens Kalchschmidt, Andrea Conte, Seol Kyoung Jung, Srinivas Ramachandran, Robert G. Roeder, Yi Shi, Rafael Casellas, Francisco J. Asturias","doi":"10.1016/j.molcel.2024.06.006","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.06.006","url":null,"abstract":"The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction. This restriction is eliminated by nuclear receptor (NR) binding to CKM-MED, which enables CTD binding in a MED26-dependent manner. Cryoelectron microscopy (cryo-EM) and crosslinking-mass spectrometry (XL-MS) revealed that the structural basis for modulation of CTD interaction with MED relates to a large intrinsically disordered region (IDR) in CKM subunit MED13 that blocks MED26 and CTD interaction with MED but is repositioned upon NR binding. Hence, NRs can control transcription initiation by priming CKM-MED for MED26-dependent RNA Pol II interaction.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489805","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}

引用次数: 0

A transient transcriptional activation governs unpolarized-to-polarized morphogenesis during embryo implantation 胚胎植入过程中，非极化到极化形态发生受瞬时转录激活的控制

IF 16 1区生物学

Molecular Cell Pub Date : 2024-07-01 DOI: 10.1016/j.molcel.2024.06.005

Xuehui Lyu, Yingzi Cui, Yinfei Kong, Min Yang, Hui Shen, Shuyun Liao, Shiyu Li, Chenrui An, Haoyi Wang, Zhe Zhang, Jennie Ong, Yan Li, Peng Du

{"title":"A transient transcriptional activation governs unpolarized-to-polarized morphogenesis during embryo implantation","authors":"Xuehui Lyu, Yingzi Cui, Yinfei Kong, Min Yang, Hui Shen, Shuyun Liao, Shiyu Li, Chenrui An, Haoyi Wang, Zhe Zhang, Jennie Ong, Yan Li, Peng Du","doi":"10.1016/j.molcel.2024.06.005","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.06.005","url":null,"abstract":"During implantation, embryos undergo an unpolarized-to-polarized transition to initiate postimplantation morphogenesis. However, the underlying molecular mechanism is unknown. Here, we identify a transient transcriptional activation governing embryonic morphogenesis and pluripotency transition during implantation. In naive pluripotent embryonic stem cells (ESCs), which represent preimplantation embryos, we find that the microprocessor component DGCR8 can recognize stem-loop structures within nascent mRNAs to sequester transcriptional coactivator FLII to suppress transcription directly. When mESCs exit from naive pluripotency, the ERK/RSK/P70S6K pathway rapidly activates, leading to FLII phosphorylation and disruption of DGCR8/FLII interaction. Phosphorylated FLII can bind to transcription factor JUN, activating cell migration-related genes to establish poised pluripotency akin to implanting embryos. Resequestration of FLII by DGCR8 drives poised ESCs into formative pluripotency. In summary, we identify a DGCR8/FLII/JUN-mediated transient transcriptional activation mechanism. Disruption of this mechanism inhibits naive-poised-formative pluripotency transition and the corresponding unpolarized-to-polarized transition during embryo implantation, which are conserved in mice and humans.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489748","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}

引用次数: 0

Phase separation as a new form of regulation in innate immunity 相分离是先天免疫调节的一种新形式

IF 16 1区生物学

Molecular Cell Pub Date : 2024-06-26 DOI: 10.1016/j.molcel.2024.06.004

Lei Wang, Wen Zhou

引用次数: 0

A cell-free transcription-translation pipeline for recreating methylation patterns boosts DNA transformation in bacteria 用于重建甲基化模式的无细胞转录-翻译管道可促进细菌的 DNA 转化

IF 16 1区生物学

Molecular Cell Pub Date : 2024-06-26 DOI: 10.1016/j.molcel.2024.06.003

Justin M. Vento, Deniz Durmusoglu, Tianyu Li, Constantinos Patinios, Sean Sullivan, Fani Ttofali, John van Schaik, Yanying Yu, Yanyan Wang, Lars Barquist, Nathan Crook, Chase L. Beisel

{"title":"A cell-free transcription-translation pipeline for recreating methylation patterns boosts DNA transformation in bacteria","authors":"Justin M. Vento, Deniz Durmusoglu, Tianyu Li, Constantinos Patinios, Sean Sullivan, Fani Ttofali, John van Schaik, Yanying Yu, Yanyan Wang, Lars Barquist, Nathan Crook, Chase L. Beisel","doi":"10.1016/j.molcel.2024.06.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.06.003","url":null,"abstract":"The bacterial world offers diverse strains for understanding medical and environmental processes and for engineering synthetic biological chassis. However, genetically manipulating these strains has faced a long-standing bottleneck: how to efficiently transform DNA. Here, we report imitating methylation patterns rapidly in TXTL (IMPRINT), a generalized, rapid, and scalable approach based on cell-free transcription-translation (TXTL) to overcome DNA restriction, a prominent barrier to transformation. IMPRINT utilizes TXTL to express DNA methyltransferases from a bacterium’s restriction-modification systems. The expressed methyltransferases then methylate DNA in vitro to match the bacterium’s DNA methylation pattern, circumventing restriction and enhancing transformation. With IMPRINT, we efficiently multiplex methylation by diverse DNA methyltransferases and enhance plasmid transformation in gram-negative and gram-positive bacteria. We also develop a high-throughput pipeline that identifies the most consequential methyltransferases, and we apply IMPRINT to screen a ribosome-binding site library in a hard-to-transform Bifidobacterium. Overall, IMPRINT can enhance DNA transformation, enabling the use of sophisticated genetic manipulation tools across the bacterial world.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453261","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}

引用次数: 0

Structure of the Hir histone chaperone complex Hir 组蛋白伴侣复合体的结构

IF 16 1区生物学

Molecular Cell Pub Date : 2024-06-25 DOI: 10.1016/j.molcel.2024.05.031

Hee Jong Kim, Mary R. Szurgot, Trevor van Eeuwen, M. Daniel Ricketts, Pratik Basnet, Athena L. Zhang, Austin Vogt, Samah Sharmin, Craig D. Kaplan, Benjamin A. Garcia, Ronen Marmorstein, Kenji Murakami

{"title":"Structure of the Hir histone chaperone complex","authors":"Hee Jong Kim, Mary R. Szurgot, Trevor van Eeuwen, M. Daniel Ricketts, Pratik Basnet, Athena L. Zhang, Austin Vogt, Samah Sharmin, Craig D. Kaplan, Benjamin A. Garcia, Ronen Marmorstein, Kenji Murakami","doi":"10.1016/j.molcel.2024.05.031","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.05.031","url":null,"abstract":"The evolutionarily conserved HIRA/Hir histone chaperone complex and ASF1a/Asf1 co-chaperone cooperate to deposit histone (H3/H4)2 tetramers on DNA for replication-independent chromatin assembly. The molecular architecture of the HIRA/Hir complex and its mode of histone deposition have remained unknown. Here, we report the cryo-EM structure of the S. cerevisiae Hir complex with Asf1/H3/H4 at 2.9–6.8 Å resolution. We find that the Hir complex forms an arc-shaped dimer with a Hir1/Hir2/Hir3/Hpc2 stoichiometry of 2/4/2/4. The core of the complex containing two Hir1/Hir2/Hir2 trimers and N-terminal segments of Hir3 forms a central cavity containing two copies of Hpc2, with one engaged by Asf1/H3/H4, in a suitable position to accommodate a histone (H3/H4)2 tetramer, while the C-terminal segments of Hir3 harbor nucleic acid binding activity to wrap DNA around the Hpc2-assisted histone tetramer. The structure suggests a model for how the Hir/Asf1 complex promotes the formation of histone tetramers for their subsequent deposition onto DNA.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448794","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}

引用次数: 0

pLxIS-containing domains are biochemically flexible regulators of interferons and metabolism 含 pLxIS 的结构域是干扰素和新陈代谢的生化灵活调节器

IF 16 1区生物学

Molecular Cell Pub Date : 2024-06-25 DOI: 10.1016/j.molcel.2024.05.030

Lauren M. Landau, Neha Chaudhary, Yun Chen Tien, Magdalena Rogozinska, Shakchhi Joshi, Conghui Yao, Joseph Crowley, Karthik Hullahalli, Ian W. Campbell, Matthew K. Waldor, Marcia Haigis, Jonathan C. Kagan

{"title":"pLxIS-containing domains are biochemically flexible regulators of interferons and metabolism","authors":"Lauren M. Landau, Neha Chaudhary, Yun Chen Tien, Magdalena Rogozinska, Shakchhi Joshi, Conghui Yao, Joseph Crowley, Karthik Hullahalli, Ian W. Campbell, Matthew K. Waldor, Marcia Haigis, Jonathan C. Kagan","doi":"10.1016/j.molcel.2024.05.030","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.05.030","url":null,"abstract":"Signal transduction proteins containing a pLxIS motif induce interferon (IFN) responses central to antiviral immunity. Apart from their established roles in activating the IFN regulator factor (IRF) transcription factors, the existence of additional pathways and functions associated with the pLxIS motif is unknown. Using a synthetic biology-based platform, we identified two orphan pLxIS-containing proteins that stimulate IFN responses independent of all known pattern-recognition receptor pathways. We further uncovered a diversity of pLxIS signaling mechanisms, where the pLxIS motif represents one component of a multi-motif signaling entity, which has variable functions in activating IRF3, the TRAF6 ubiquitin ligase, IκB kinases, mitogen-activated protein kinases, and metabolic activities. The most diverse pLxIS signaling mechanisms were associated with the highest antiviral activities in human cells. The flexibility of domains that regulate IFN signaling may explain their prevalence in nature.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448808","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}

引用次数: 0

PELI2 is a negative regulator of STING signaling that is dynamically repressed during viral infection PELI2 是 STING 信号的负调控因子，在病毒感染期间受到动态抑制

IF 16 1区生物学

Molecular Cell Pub Date : 2024-06-24 DOI: 10.1016/j.molcel.2024.06.001

Christopher Ritchie, Lingyin Li

引用次数: 0