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The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation H3.3K36M 同源组蛋白通过 DNA 甲基化的丧失破坏表观遗传记忆的建立
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-04 DOI: 10.1016/j.molcel.2024.09.015
Joydeb Sinha, Jan F. Nickels, Abby R. Thurm, Connor H. Ludwig, Bella N. Archibald, Michaela M. Hinks, Jun Wan, Dong Fang, Lacramioara Bintu
{"title":"The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation","authors":"Joydeb Sinha, Jan F. Nickels, Abby R. Thurm, Connor H. Ludwig, Bella N. Archibald, Michaela M. Hinks, Jun Wan, Dong Fang, Lacramioara Bintu","doi":"10.1016/j.molcel.2024.09.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.015","url":null,"abstract":"Histone H3.3 is frequently mutated in tumors, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the epigenetic landscape, its effects on gene expression dynamics remain unclear. Here, we use a synthetic reporter to measure the effects of H3.3K36M on silencing and epigenetic memory after recruitment of the ZNF10 Krüppel-associated box (KRAB) domain, part of the largest class of human repressors and associated with H3K9me3 deposition. We find that H3.3K36M, which decreases H3K36 methylation and increases histone acetylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a model for establishment and maintenance of epigenetic memory, where the H3K36 methylation pathway is necessary to maintain histone deacetylation and convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374104","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
The structural landscape of Microprocessor-mediated processing of pri-let-7 miRNAs 微处理器介导的 pri-let-7 miRNA 处理结构图
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-04 DOI: 10.1016/j.molcel.2024.09.008
Ankur Garg, Renfu Shang, Todor Cvetanovic, Eric C. Lai, Leemor Joshua-Tor
{"title":"The structural landscape of Microprocessor-mediated processing of pri-let-7 miRNAs","authors":"Ankur Garg, Renfu Shang, Todor Cvetanovic, Eric C. Lai, Leemor Joshua-Tor","doi":"10.1016/j.molcel.2024.09.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.008","url":null,"abstract":"MicroRNA (miRNA) biogenesis is initiated upon cleavage of a primary miRNA (pri-miRNA) hairpin by the Microprocessor (MP), composed of the Drosha RNase III enzyme and its partner DGCR8. Multiple pri-miRNA sequence motifs affect MP recognition, fidelity, and efficiency. Here, we performed cryoelectron microscopy (cryo-EM) and biochemical studies of several let-7 family pri-miRNAs in complex with human MP. We show that MP has the structural plasticity to accommodate a range of pri-miRNAs. These structures revealed key features of the 5′ UG sequence motif, more comprehensively represented as the “flipped U with paired N” (fUN) motif. Our analysis explains how cleavage of class-II pri-let-7 members harboring a bulged nucleotide generates a non-canonical precursor with a 1-nt 3′ overhang. Finally, the MP-SRSF3-pri-let-7f1 structure reveals how SRSF3 contributes to MP fidelity by interacting with the CNNC motif and Drosha’s Piwi/Argonaute/Zwille (PAZ)-like domain. Overall, this study sheds light on the mechanisms for flexible recognition, accurate cleavage, and regulated processing of different pri-miRNAs by MP.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374106","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
Cell-cycle-dependent mRNA localization in P-bodies 细胞周期依赖的 mRNA 在 P 体内的定位
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-04 DOI: 10.1016/j.molcel.2024.09.011
Adham Safieddine, Marie-Noëlle Benassy, Thomas Bonte, Floric Slimani, Oriane Pourcelot, Michel Kress, Michèle Ernoult-Lange, Maïté Courel, Emeline Coleno, Arthur Imbert, Antoine Laine, Annie Munier Godebert, Angelique Vinit, Corinne Blugeon, Guillaume Chevreux, Daniel Gautheret, Thomas Walter, Edouard Bertrand, Marianne Bénard, Dominique Weil
{"title":"Cell-cycle-dependent mRNA localization in P-bodies","authors":"Adham Safieddine, Marie-Noëlle Benassy, Thomas Bonte, Floric Slimani, Oriane Pourcelot, Michel Kress, Michèle Ernoult-Lange, Maïté Courel, Emeline Coleno, Arthur Imbert, Antoine Laine, Annie Munier Godebert, Angelique Vinit, Corinne Blugeon, Guillaume Chevreux, Daniel Gautheret, Thomas Walter, Edouard Bertrand, Marianne Bénard, Dominique Weil","doi":"10.1016/j.molcel.2024.09.011","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.011","url":null,"abstract":"Understanding the dynamics of RNA targeting to membraneless organelles is essential to disentangle their functions. Here, we investigate how P-bodies (PBs) evolve during cell-cycle progression in HEK293 cells. PB purification across the cell cycle uncovers widespread changes in their RNA content, partly uncoupled from cell-cycle-dependent changes in RNA expression. Single-molecule fluorescence <em>in situ</em> hybridization (FISH) shows various mRNA localization patterns in PBs peaking in G1, S, or G2, with examples illustrating the timely capture of mRNAs in PBs when their encoded protein becomes dispensable. Rather than directly reflecting absence of translation, cyclic mRNA localization in PBs can be controlled by RBPs, such as HuR in G2, and by RNA features. Indeed, while PB mRNAs are AU rich at all cell-cycle phases, they are specifically longer in G1, possibly related to post-mitotic PB reassembly. Altogether, our study supports a model where PBs are more than a default location for excess untranslated mRNAs.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374105","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
The challenges of investigating RNA function 研究 RNA 功能面临的挑战
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.08.019
Li Yang, Igor Ulitsky, Wendy V. Gilbert, Chengqi Yi, Jernej Ule, Maïwen Caudron-Herger
{"title":"The challenges of investigating RNA function","authors":"Li Yang, Igor Ulitsky, Wendy V. Gilbert, Chengqi Yi, Jernej Ule, Maïwen Caudron-Herger","doi":"10.1016/j.molcel.2024.08.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.019","url":null,"abstract":"High-throughput sequencing methods have led to the discovery of many non-coding RNAs, RNA modifications, and protein-RNA interactions. While the list keeps growing, the challenge of determining their functions remains. For our <span><span>focus issue on RNA biology</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>, we spoke with several researchers about their perspective on investigating the functions of RNA.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369134","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
PRC2-RNA interactions: Viewpoint from Tom Cech, Chen Davidovich, and Richard Jenner PRC2-RNA 相互作用：Tom Cech、Chen Davidovich 和 Richard Jenner 的观点
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.09.010
Thomas R. Cech, Chen Davidovich, Richard G. Jenner
{"title":"PRC2-RNA interactions: Viewpoint from Tom Cech, Chen Davidovich, and Richard Jenner","authors":"Thomas R. Cech, Chen Davidovich, Richard G. Jenner","doi":"10.1016/j.molcel.2024.09.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.010","url":null,"abstract":"Diverse biochemical, structural, and <em>in vivo</em> data support models for the regulation of polycomb repressive complex 2 (PRC2) activity by RNAs, which may contribute to the maintenance of epigenetic states. Here, we summarize this research and also suggest why it can be difficult to capture biologically relevant PRC2-RNA interactions in living cells.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369140","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
RNA-driven phase transitions in biomolecular condensates 生物分子凝聚体中的 RNA 驱动相变
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.09.005
Gable M. Wadsworth, Sukanya Srinivasan, Lien B. Lai, Moulisubhro Datta, Venkat Gopalan, Priya R. Banerjee
{"title":"RNA-driven phase transitions in biomolecular condensates","authors":"Gable M. Wadsworth, Sukanya Srinivasan, Lien B. Lai, Moulisubhro Datta, Venkat Gopalan, Priya R. Banerjee","doi":"10.1016/j.molcel.2024.09.005","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.005","url":null,"abstract":"RNAs and RNA-binding proteins can undergo spontaneous or active condensation into phase-separated liquid-like droplets. These condensates are cellular hubs for various physiological processes, and their dysregulation leads to diseases. Although RNAs are core components of many cellular condensates, the underlying molecular determinants for the formation, regulation, and function of ribonucleoprotein condensates have largely been studied from a protein-centric perspective. Here, we highlight recent developments in ribonucleoprotein condensate biology with a particular emphasis on RNA-driven phase transitions. We also present emerging future directions that might shed light on the role of RNA condensates in spatiotemporal regulation of cellular processes and inspire bioengineering of RNA-based therapeutics.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369674","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
Timing is everything: When is m6A deposited? 时间就是一切：何时存放 m6A？
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.09.012
David Dierks, Schraga Schwartz
{"title":"Timing is everything: When is m6A deposited?","authors":"David Dierks, Schraga Schwartz","doi":"10.1016/j.molcel.2024.09.012","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.012","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, Tang et al. suggest that m6A deposition is predominantly post-transcriptional.<span><span><sup>1</sup></span></span> They further propose that nuclear dwell time dictates the post-transcriptional accumulation of m6A. These findings have important implications for m6A biogenesis and function.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369135","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
PKM2-G-quadruplex interactions conspire to regulate the cancer transcriptome PKM2-G-四叠体相互作用共同调控癌症转录组
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.09.013
Prakash Kharel, Pavel Ivanov
{"title":"PKM2-G-quadruplex interactions conspire to regulate the cancer transcriptome","authors":"Prakash Kharel, Pavel Ivanov","doi":"10.1016/j.molcel.2024.09.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.013","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, Anastasakis et al. describe a novel function of the metabolic enzyme PKM2 as an RNA G-quadruplex binding protein, which could contribute to cancer biology.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369136","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
50 years in the making: acp3U, an amino-acid-containing nucleoside, links N-glycans and RNA in glycoRNA 50 年历程：含氨基酸的核苷 acp3U 在糖核糖核酸中将 N-糖和核糖核酸连接起来
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.09.014
Kfir B. Steinbuch, Yitzhak Tor
{"title":"50 years in the making: acp3U, an amino-acid-containing nucleoside, links N-glycans and RNA in glycoRNA","authors":"Kfir B. Steinbuch, Yitzhak Tor","doi":"10.1016/j.molcel.2024.09.014","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.014","url":null,"abstract":"In a recent publication in <em>Cell</em>, Xie et al.<span><span><sup>1</sup></span></span> report a sensitive and scalable method for the detection and characterization of native glycoRNAs and identify acp<sup>3</sup>U, an abundant modified nucleoside discovered 50 years ago in tRNA<sup>Phe</sup>, as one of the primary attachment sites for N-glycans.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369137","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
Nuclear sorting of short RNA polymerase II transcripts 短 RNA 聚合酶 II 转录本的核分选
IF 16 1区 生物学
Molecular Cell Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.08.024
William Garland, Torben Heick Jensen
{"title":"Nuclear sorting of short RNA polymerase II transcripts","authors":"William Garland, Torben Heick Jensen","doi":"10.1016/j.molcel.2024.08.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.024","url":null,"abstract":"Mammalian genomes produce an abundance of short RNA. This is, to a large extent, due to the genome-wide and spurious activity of RNA polymerase II (RNAPII). However, it is also because the vast majority of initiating RNAPII, regardless of the transcribed DNA unit, terminates within a ∼3-kb early “pausing zone.” Given that the resultant RNAs constitute both functional and non-functional species, their proper sorting is critical. One way to think about such quality control (QC) is that transcripts, from their first emergence, are relentlessly targeted by decay factors, which may only be avoided by engaging protective processing pathways. In a molecular materialization of this concept, recent progress has found that both “destructive” and “productive” RNA effectors assemble at the 5′ end of capped RNA, orchestrated by the essential arsenite resistance protein 2 (ARS2) protein. Based on this principle, we here discuss early QC mechanisms and how these might sort short RNAs to their final fates.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369144","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
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