Molecular Cell最新文献_第2页

Tackling a textbook example of multistep enzyme catalysis with deep learning-driven design

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-03 DOI: 10.1016/j.molcel.2025.03.012

Boje Ingwersen, Birte Höcker

引用次数: 0

Ultrastable and versatile multimeric ensembles of FoxP3 on microsatellites 微卫星上的 FoxP3 超稳定多功能多聚体组合

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-02 DOI: 10.1016/j.molcel.2025.03.005

Fangwei Leng, Raquel Merino-Urteaga, Xi Wang, Wenxiang Zhang, Taekjip Ha, Sun Hur

{"title":"Ultrastable and versatile multimeric ensembles of FoxP3 on microsatellites","authors":"Fangwei Leng, Raquel Merino-Urteaga, Xi Wang, Wenxiang Zhang, Taekjip Ha, Sun Hur","doi":"10.1016/j.molcel.2025.03.005","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.005","url":null,"abstract":"Microsatellites are essential genomic components increasingly linked to transcriptional regulation. FoxP3, a transcription factor critical for regulatory T cell (Treg) development, recognizes TTTG repeat microsatellites by forming multimers along DNA. However, FoxP3 also binds a broader range of TnG repeats (n = 2–5), often at the edges of accessible chromatin regions. This raises questions about how FoxP3 adapts to sequence variability and the potential role of nucleosomes. Using cryoelectron microscopy and single-molecule analyses, we show that murine FoxP3 assembles into various distinct supramolecular structures, depending on DNA sequence. This structural plasticity enables FoxP3 to bridge 2–4 DNA duplexes, forming ultrastable structures that coordinate multiple genomic loci. Nucleosomes further facilitate FoxP3 assembly by inducing local DNA bending, creating a nucleus that recruits distal DNA elements through multiway bridging. Our findings thus reveal FoxP3’s unusual ability to shapeshift to accommodate evolutionarily dynamic microsatellites and its potential to reinforce chromatin boundaries and three-dimensional genomic architecture.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"97 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758393","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

Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-26 DOI: 10.1016/j.molcel.2025.03.004

Luke Lambourne, Kaia Mattioli, Clarissa Santoso, Gloria Sheynkman, Sachi Inukai, Babita Kaundal, Anna Berenson, Kerstin Spirohn-Fitzgerald, Anukana Bhattacharjee, Elisabeth Rothman, Shaleen Shrestha, Florent Laval, Brent S. Carroll, Stephen P. Plassmeyer, Ryan J. Emenecker, Zhipeng Yang, Deepa Bisht, Jared A. Sewell, Guangyuan Li, Anisa Prasad, Juan I. Fuxman Bass

{"title":"Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms","authors":"Luke Lambourne, Kaia Mattioli, Clarissa Santoso, Gloria Sheynkman, Sachi Inukai, Babita Kaundal, Anna Berenson, Kerstin Spirohn-Fitzgerald, Anukana Bhattacharjee, Elisabeth Rothman, Shaleen Shrestha, Florent Laval, Brent S. Carroll, Stephen P. Plassmeyer, Ryan J. Emenecker, Zhipeng Yang, Deepa Bisht, Jared A. Sewell, Guangyuan Li, Anisa Prasad, Juan I. Fuxman Bass","doi":"10.1016/j.molcel.2025.03.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.004","url":null,"abstract":"Most human transcription factor (TF) genes encode multiple protein isoforms differing in DNA-binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: “rewirers” and “negative regulators,” both of which were associated with differentiation and cancer. Our results support a model wherein the relative expression levels of, and interactions involving, TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"35 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703188","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

Three-dimensional regulatory hubs support oncogenic programs in glioblastoma

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-26 DOI: 10.1016/j.molcel.2025.03.007

Sarah L. Breves, Dafne Campigli Di Giammartino, James Nicholson, Stefano Cirigliano, Syed Raza Mahmood, Uk Jin Lee, Alexander Martinez-Fundichely, Johannes Jungverdorben, Richa Singhania, Sandy Rajkumar, Raphael Kirou, Lorenz Studer, Ekta Khurana, Alexander Polyzos, Howard A. Fine, Effie Apostolou

{"title":"Three-dimensional regulatory hubs support oncogenic programs in glioblastoma","authors":"Sarah L. Breves, Dafne Campigli Di Giammartino, James Nicholson, Stefano Cirigliano, Syed Raza Mahmood, Uk Jin Lee, Alexander Martinez-Fundichely, Johannes Jungverdorben, Richa Singhania, Sandy Rajkumar, Raphael Kirou, Lorenz Studer, Ekta Khurana, Alexander Polyzos, Howard A. Fine, Effie Apostolou","doi":"10.1016/j.molcel.2025.03.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.007","url":null,"abstract":"Dysregulation of enhancer-promoter communication in the three-dimensional (3D) nucleus is increasingly recognized as a potential driver of oncogenic programs. Here, we profiled the 3D enhancer-promoter networks of patient-derived glioblastoma stem cells to identify central regulatory nodes. We focused on hyperconnected 3D hubs and demonstrated that hub-interacting genes exhibit high and coordinated expression at the single-cell level and are associated with oncogenic programs that distinguish glioblastoma from low-grade glioma. Epigenetic silencing of a recurrent hub—with an uncharacterized role in glioblastoma—was sufficient to cause downregulation of hub-connected genes, shifts in transcriptional states, and reduced clonogenicity. Integration of datasets across 16 cancers identified “universal” and cancer-type-specific 3D hubs that enrich for oncogenic programs and factors associated with worse prognosis. Genetic alterations could explain only a small fraction of hub hyperconnectivity and increased activity. Overall, our study provides strong support for the potential central role of 3D regulatory hubs in controlling oncogenic programs and properties.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"215 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703192","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

Rapid folding of nascent RNA regulates eukaryotic RNA biogenesis

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-25 DOI: 10.1016/j.molcel.2025.02.025

Leonard Schärfen, Isaac W. Vock, Matthew D. Simon, Karla M. Neugebauer

{"title":"Rapid folding of nascent RNA regulates eukaryotic RNA biogenesis","authors":"Leonard Schärfen, Isaac W. Vock, Matthew D. Simon, Karla M. Neugebauer","doi":"10.1016/j.molcel.2025.02.025","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.025","url":null,"abstract":"RNA’s catalytic, regulatory, or coding potential depends on structure formation. Because base pairing occurs during transcription, early structural states can govern RNA processing events and dictate the formation of functional conformations. These co-transcriptional states remain mostly unknown. Here, we develop co-transcriptional structure tracking (CoSTseq), which detects nascent RNA base pairing within and upon exit from RNA polymerases (Pols) transcriptome wide in living yeast cells. Monitoring each nucleotide’s base pairing activity during transcription, CoSTseq reveals predominantly rapid pairing—within 25 bp of transcription after addition to the nascent chain. Moreover, ∼23% of rRNA nucleotides attain their final base pairing state near Pol I, while most other nucleotides must undergo changes in pairing status during later steps of ribosome biogenesis. We show that helicases act immediately to remodel structures across the rDNA locus to facilitate ribosome biogenesis. By contrast, nascent pre-mRNAs attain local structures indistinguishable from mature mRNAs, suggesting that refolding behind elongating ribosomes resembles co-transcriptional folding behind Pol II.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"97 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695626","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

Amplified dosage of the NKX2-1 lineage transcription factor controls its oncogenic role in lung adenocarcinoma

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-25 DOI: 10.1016/j.molcel.2025.03.001

John L. Pulice, Matthew Meyerson

引用次数: 0

UbiREAD deciphers proteasomal degradation code of homotypic and branched K48 and K63 ubiquitin chains

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-24 DOI: 10.1016/j.molcel.2025.02.021

Leo Kiss, Leo C. James, Brenda A. Schulman

{"title":"UbiREAD deciphers proteasomal degradation code of homotypic and branched K48 and K63 ubiquitin chains","authors":"Leo Kiss, Leo C. James, Brenda A. Schulman","doi":"10.1016/j.molcel.2025.02.021","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.021","url":null,"abstract":"Ubiquitin chains define the fates of their modified proteins, often mediating proteasomal degradation in eukaryotes. Yet heterogeneity of intracellular ubiquitination has precluded systematically comparing the degradation capacities of different ubiquitin chains. We developed ubiquitinated reporter evaluation after intracellular delivery (UbiREAD), a technology that monitors cellular degradation and deubiquitination at high temporal resolution after bespoke ubiquitinated proteins are delivered into human cells. Comparing the degradation of a model substrate modified with various K48, K63, or K48/K63-branched ubiquitin chains revealed fundamental differences in their intracellular degradation capacities. K48 chains with three or more ubiquitins triggered degradation within minutes. K63-ubiquitinated substrate was rapidly deubiquitinated rather than degraded. Surprisingly, in K48/K63-branched chains, substrate-anchored chain identity determined the degradation and deubiquitination behavior, establishing that branched chains are not the sum of their parts. UbiREAD reveals a degradation code for ubiquitin chains varying by linkage, length, and topology and a functional hierarchy within branched ubiquitin chains.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"61 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677851","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

PI3Kβ functions as a protein kinase to promote cellular protein O-GlcNAcylation and acetyl-CoA production for tumor growth

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-24 DOI: 10.1016/j.molcel.2025.02.024

Xuxiao He, Deyu Chen, Guijun Liu, Qingang Wu, Hong Zhao, Dong Guo, Xiaoming Jiang, Min Li, Ying Meng, Yucheng Yin, Xianglai Ye, Shudi Luo, Yan Xia, Tony Hunter, Zhimin Lu

{"title":"PI3Kβ functions as a protein kinase to promote cellular protein O-GlcNAcylation and acetyl-CoA production for tumor growth","authors":"Xuxiao He, Deyu Chen, Guijun Liu, Qingang Wu, Hong Zhao, Dong Guo, Xiaoming Jiang, Min Li, Ying Meng, Yucheng Yin, Xianglai Ye, Shudi Luo, Yan Xia, Tony Hunter, Zhimin Lu","doi":"10.1016/j.molcel.2025.02.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.024","url":null,"abstract":"Phosphatidylinositol 3-kinase (PI3K) phosphorylates PI(4,5)P2 to produce PI(3,4,5)P3, thereby activating AKT and other effector proteins. However, whether PI3K has non-PI(3,4,5)P3-related functions critical for tumor development remains unclear. Here, we demonstrate that high glucose induces PI3Kβ binding to O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) in glioblastoma cells, dependent on hexokinase 1 (HK1)-mediated OGT Y889 phosphorylation and subsequent p85α recruitment. Importantly, PI3Kβ functions as a protein kinase, phosphorylating OGT at T985 and enhancing OGT activity and total cellular protein O-GlcNAcylation. Activated OGT O-GlcNAcylates ATP-citrate synthase (ACLY) at T639 and S667, leading to ACLY activation-dependent acetyl-coenzyme A (CoA) production to increase fatty acid levels and histone H3 acetylation for gene transcription. Intervention in PI3Kβ-mediated OGT phosphorylation and ACLY O-GlcNAcylation inhibits glioblastoma cell proliferation and tumor growth in xenografts. These findings underscore the critical role of PI3Kβ in governing protein O-GlcNAcylation, fatty acid metabolism, and chromatin modification through its protein kinase activity and provide instrumental insight into the roles of PI3K in tumor progression.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"71 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677853","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

Proteome-wide discovery of phage anti-defense proteins by Alphafold2

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.020

Zhifu Han, Yu Cao, Jijie Chai

引用次数: 0

A cut above: Bacterial deubiquitinases with ubiquitin clippase activity

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.023

Mark Hochstrasser

引用次数: 0