EMBO Reports最新文献

The actin nucleation promoting factor WASH facilitates clathrin-independent endocytosis of human papillomaviruses. 肌动蛋白成核促进因子WASH促进人乳头瘤病毒不依赖网格蛋白的内吞作用。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-10 DOI: 10.1038/s44319-025-00594-3

Pia Brinkert, Lena Krebs, Pilar Samperio Ventayol, Lilo Greune, Carina Bannach, Cynthia Amakiri, Delia Bucher, Jana Kollasser, Petra Dersch, Steeve Boulant, Theresia E B Stradal, Mario Schelhaas

{"title":"The actin nucleation promoting factor WASH facilitates clathrin-independent endocytosis of human papillomaviruses.","authors":"Pia Brinkert, Lena Krebs, Pilar Samperio Ventayol, Lilo Greune, Carina Bannach, Cynthia Amakiri, Delia Bucher, Jana Kollasser, Petra Dersch, Steeve Boulant, Theresia E B Stradal, Mario Schelhaas","doi":"10.1038/s44319-025-00594-3","DOIUrl":"https://doi.org/10.1038/s44319-025-00594-3","url":null,"abstract":"Endocytosis is a fundamental cellular process facilitated by diverse mechanisms. Remarkably, several distinct clathrin-independent endocytic processes have been identified and characterized following virus uptake into cells. For some, however, mechanistic execution and biological function remain largely unclear. This includes an endocytic process exploited by human papillomavirus type 16 (HPV16). Using HPV16, we examine how vesicles are formed by combining systematic cellular perturbations with electron and video microscopy. Cargo uptake occurs by uncoated, inward-budding pits. Mechanistically, vesicle scission is facilitated by actin polymerization controlled through the actin nucleation-promoting factor WASH. While WASH typically functions in conjunction with the retromer complex on endosomes during retrograde trafficking, endocytic vesicle formation is largely independent of retromer itself and the heterodimeric membrane-bending SNX-BAR retromer adaptor, thereby uncovering a role of WASH in endocytosis in addition to its canonical role in intracellular membrane trafficking.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274173","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

White and brown adipose tissue share a convergent fibro-adipogenic progenitor population. 白色和棕色脂肪组织共享一个趋同的纤维脂肪祖细胞群。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-08 DOI: 10.1038/s44319-025-00591-6

Hoang V Bui, Julia K Hansen, Valentina Lo Sardo, Andrea Galmozzi

{"title":"White and brown adipose tissue share a convergent fibro-adipogenic progenitor population.","authors":"Hoang V Bui, Julia K Hansen, Valentina Lo Sardo, Andrea Galmozzi","doi":"10.1038/s44319-025-00591-6","DOIUrl":"10.1038/s44319-025-00591-6","url":null,"abstract":"Adipose tissue heterogeneity has emerged as a central factor in regulating adipose tissue function in physiology and pathophysiology, yet tools to model and study this diversity in vitro remain limited. Here, we performed single-cell RNA sequencing on cultured primary white and brown preadipocytes to assess how in vitro conditions impact progenitor identity. We identified two major subpopulations in both depots: committed adipogenic precursors (CAPs) and fibro-adipogenic progenitor-like cells (FAPLs). Remarkably, FAPLs were also present in brown adipose tissue, expanding the known landscape of progenitor populations in this depot. Trajectory and regulon analyses revealed that both white and brown FAPLs exhibit similar pro-fibrotic, stress-responsive signatures and diverge early from proliferating progenitor states. Integration of datasets showed that FAPLs from both depots cluster together, emphasizing their conserved identity, while CAPs remain depot-specific. Comparison to previously published in vivo single-cell datasets revealed that these in vitro populations, including brown adipose FAPLs, correspond to adipose-resident progenitor subtypes, validating the physiological relevance of this model for studying adipose tissue heterogeneity and development.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.2,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250269","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

Arginine methylation-dependent METTL14-SMN interaction regulates RNA m⁶A homeostasis. 精氨酸甲基化依赖的METTL14-SMN相互作用调节RNA m6A稳态。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-06 DOI: 10.1038/s44319-025-00590-7

Yi Zhang, Lei Shen, Lili Ren, Jiangbo Wei, Hoang Quoc Hai Pham, Xiaoqun Tao, Jiamin Guo, Zhihao Wang, Binghui Shen, Rui Su, Chuan He, Yanzhong Yang

{"title":"Arginine methylation-dependent METTL14-SMN interaction regulates RNA m6A homeostasis.","authors":"Yi Zhang, Lei Shen, Lili Ren, Jiangbo Wei, Hoang Quoc Hai Pham, Xiaoqun Tao, Jiamin Guo, Zhihao Wang, Binghui Shen, Rui Su, Chuan He, Yanzhong Yang","doi":"10.1038/s44319-025-00590-7","DOIUrl":"https://doi.org/10.1038/s44319-025-00590-7","url":null,"abstract":"N6-methyladenosine (m6A) homeostasis is essential for development, and its dysregulation is linked to cancers and neurological disorders. However, the mechanisms regulating m6A remain unclear. Here, we identify the survival of motoneuron (SMN) protein as a novel interaction partner of METTL14, a key component of the m6A methyltransferase complex. SMN binds METTL14 via its Tudor domain in an arginine methylation-dependent manner. Mutations in the SMN Tudor domain identified in spinal muscular atrophy (SMA) disrupt its interaction with METTL14 and reduce m6A levels in patient-derived fibroblasts, linking m6A dysregulation to SMA pathology. Both SMN knockdown and SMA mutations impair m6A deposition on the mRNAs of DNA repair genes, mirroring the effects of METTL14 hypomethylation. Consequently, SMA patient fibroblasts are hypersensitive to DNA-damaging agents due to reduced levels of DNA repair gene expression. To explore the function of METTL14 arginine methylation in vivo, we generated a Mettl14 methylation-deficient mouse model (Mettl14RK). Although this model does not show SMA-like phenotypes, the mutants are partially embryonic lethal and show abnormal hematopoiesis, underscoring a role for methylated METTL14 in early development.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238250","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

Aging impairs the antiviral defense in Caenorhabditis elegans due to loss of DRH-1/RIG-I deSUMOylation by ULP-4/SENP7. 衰老会损害秀丽隐杆线虫的抗病毒防御，这是由于ULP-4/SENP7失去DRH-1/ rig -1 deSUMOylation。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-02 DOI: 10.1038/s44319-025-00589-0

Yun Zhang, Andrew V Samuelson

{"title":"Aging impairs the antiviral defense in Caenorhabditis elegans due to loss of DRH-1/RIG-I deSUMOylation by ULP-4/SENP7.","authors":"Yun Zhang, Andrew V Samuelson","doi":"10.1038/s44319-025-00589-0","DOIUrl":"10.1038/s44319-025-00589-0","url":null,"abstract":"Innate immune defense relies on post-translational modifications (PTMs) to protect against viral infections. SUMOylation plays complex roles in viral replication and antiviral defenses in mammals and has been implicated in age-associated diseases. Whether PTMs and SUMOylation contribute to age-induced immunosenescence is unknown. We find that antiviral defense in Caenorhabditis elegans is regulated through SUMOylation of DRH-1, ortholog of the cytosolic pattern recognition receptor RIG-I. The SUMO isopeptidase ULP-4 is essential for deSUMOylation of DRH-1 and activation of the intracellular pathogen response (IPR) after exposure to Orsay virus (OV). ULP-4 stabilizes DRH-1, which translocates to the mitochondria to activate the IPR. Loss of drh-1 or ulp-4 compromises antiviral defense; mutant animals fail to clear OV and develop intestinal pathogenesis. During aging, ulp-4 expression decreases, which promotes DRH-1 proteosomal degradation and IPR loss. Mutating the DRH-1 SUMOylated lysines partially rescued the age-associated lost inducibility of the IPR. Our work establishes that aging results in dysregulated SUMOylation and loss of DRH-1, which compromises antiviral defense and creates a physiological shift to favor chronic pathological infection in older animals.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211970","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

Distinct amyloid fibril structures formed by ALS-causing SOD1 mutants G93A and D101N. 引起als的SOD1突变体G93A和D101N形成不同的淀粉样蛋白纤维结构。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-01 Epub Date: 2025-08-26 DOI: 10.1038/s44319-025-00557-8

Mu-Ya Zhang, Yeyang Ma, Li-Qiang Wang, Wencheng Xia, Xiang-Ning Li, Kun Zhao, Jie Chen, Dan Li, Liangyu Zou, Zhengzhi Wang, Cong Liu, Yi Liang

{"title":"Distinct amyloid fibril structures formed by ALS-causing SOD1 mutants G93A and D101N.","authors":"Mu-Ya Zhang, Yeyang Ma, Li-Qiang Wang, Wencheng Xia, Xiang-Ning Li, Kun Zhao, Jie Chen, Dan Li, Liangyu Zou, Zhengzhi Wang, Cong Liu, Yi Liang","doi":"10.1038/s44319-025-00557-8","DOIUrl":"10.1038/s44319-025-00557-8","url":null,"abstract":"Two hundred eight genetic mutations in SOD1 have been linked to amyotrophic lateral sclerosis (ALS). Of these, the G93A and D101N variants maintain much of their physiological function, closely resembling that of wild-type SOD1, and the SOD1-G93A transgenic mouse is the most extensively used mouse line in the study of ALS. In this study, we report two cryo-EM structures of amyloid fibrils formed by G93A and D101N mutants of SOD1 protein. These mutations give rise to amyloid fibrils with distinct structures compared to native SOD1 fibrils. The fibril core displays a serpentine configuration featuring four β-strands, held together by two hydrophobic cavities and a salt bridge between Arg143 and Asp96 in the G93A fibril, and by a hydrophobic cavity and a salt bridge between Arg143 and Asp132 in the D101N fibril, demonstrating unique structural features for each mutant. Moreover, our results show that G93A fibrils are significantly more toxic than those formed by D101N, which do not show a marked increase in toxicity compared to wild-type SOD1 fibrils. This study sheds light on the structural mechanisms through which SOD1 mutants aggregate and induce cytotoxicity in ALS.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4820-4846"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946985","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}

引用次数: 0

Symbionts with eroded genomes adjust gene expression according to host life-stage and environment. 基因组被侵蚀的共生体会根据宿主的生命阶段和环境调整基因表达。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-01 Epub Date: 2025-08-08 DOI: 10.1038/s44319-025-00525-2

Ana S P Carvalho, Sinah T Wingert, Roy Kirsch, Heiko Vogel, Gregor Kölsch, Martin Kaltenpoth

{"title":"Symbionts with eroded genomes adjust gene expression according to host life-stage and environment.","authors":"Ana S P Carvalho, Sinah T Wingert, Roy Kirsch, Heiko Vogel, Gregor Kölsch, Martin Kaltenpoth","doi":"10.1038/s44319-025-00525-2","DOIUrl":"10.1038/s44319-025-00525-2","url":null,"abstract":"Symbiotic bacteria in long-term host associations frequently undergo extreme genome reduction. While they retain genes beneficial to the host, their repertoire of transcription factors is severely reduced. Here, we assessed whether genome-eroded symbionts can still regulate gene expression by characterizing the transcriptional responses of obligate symbionts in reed beetles to different temperatures and host life stages. These symbionts feature a small genome (~0.5 Mb), encoding for 9-10 essential amino acid biosynthesis pathways, 0-2 pectinases, and 4-5 transcription factors. We found that the symbionts respond to winter conditions by upregulating a heat-shock sigma factor and downregulating translation machinery. Across life stages, symbionts adjusted gene expression to meet the hosts' nutritional demands, upregulating amino acid biosynthesis in larvae, while expression and activity of host and symbiont enzymes involved in plant cell wall breakdown increased in the folivorous adults. In addition, the regulation of symbiont cell morphology genes corresponded to cell shape differences across life stages. Thus, reed beetle symbionts may use their few transcription factors to respond to the host's environment, highlighting the regulatory potential of long-term coevolved symbionts despite severely reduced genomes.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4656-4674"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803794","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}

引用次数: 0

SRAS1.1 E3 ligase mediates DSK2A degradation to regulate autophagy and drought tolerance in Arabidopsis. SRAS1.1 E3连接酶介导DSK2A降解调控拟南芥自噬和耐旱性。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-01 Epub Date: 2025-08-22 DOI: 10.1038/s44319-025-00556-9

Xiao-Hu Li, Meng Wang, Yi-Ran Xu, Qian-Huan Guo, Peng Liu, Chang-Ai Wu, Guo-Dong Yang, Jin-Guang Huang, Shi-Zhong Zhang, Cheng-Chao Zheng, Kang Yan

{"title":"SRAS1.1 E3 ligase mediates DSK2A degradation to regulate autophagy and drought tolerance in Arabidopsis.","authors":"Xiao-Hu Li, Meng Wang, Yi-Ran Xu, Qian-Huan Guo, Peng Liu, Chang-Ai Wu, Guo-Dong Yang, Jin-Guang Huang, Shi-Zhong Zhang, Cheng-Chao Zheng, Kang Yan","doi":"10.1038/s44319-025-00556-9","DOIUrl":"10.1038/s44319-025-00556-9","url":null,"abstract":"Drought stress significantly impacts plant growth and productivity, requiring complex adaptive responses to ensure survival. In eukaryotes, autophagy and the ubiquitin-proteasome system (UPS) are critical pathways for maintaining cellular homeostasis under stress. While their interaction is well-studied in animals, it remains poorly understood in plants, particularly under drought conditions. Here, we identify the E3 ubiquitin ligase SRAS1.1 as a key regulator of selective autophagy and drought tolerance in Arabidopsis, mediating its function through the ubiquitination and degradation of the autophagy receptor DSK2A. Loss of SRAS1.1 enhances drought tolerance by reducing water loss, increasing survival rates, and accelerating flowering. SRAS1.1 directly interacts with and ubiquitinates the autophagy receptor DSK2A, promoting its degradation via the 26S proteasome. Notably, under drought stress, SRAS1.1 relocates from the nucleus to the cytoplasm, associates with autophagosomes, and modulates autophagy-related gene expression and BES1 accumulation. These findings provide novel insights into UPS-autophagy crosstalk in plants and highlight SRAS1.1 as a promising target for genetic engineering to develop drought-resilient crops and to advance sustainable agriculture.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4794-4819"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946994","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}

引用次数: 0

The CGG triplet repeat binding protein 1 counteracts R-loop induced transcription-replication stress. CGG三联体重复结合蛋白1抵消r环诱导的转录复制胁迫。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-01 Epub Date: 2025-08-26 DOI: 10.1038/s44319-025-00550-1

Henning Ummethum, Augusto C Murriello, Marcel Werner, Elizabeth Márquez-Gómez, Ann-Christine König, Elisabeth Kruse, Maxime Lalonde, Manuel Trauner, Anna Chanou, Matthias Weiβ, Clare S K Lee, Andreas Ettinger, Florian Erhard, Stefanie M Hauck, Stephan Hamperl

{"title":"The CGG triplet repeat binding protein 1 counteracts R-loop induced transcription-replication stress.","authors":"Henning Ummethum, Augusto C Murriello, Marcel Werner, Elizabeth Márquez-Gómez, Ann-Christine König, Elisabeth Kruse, Maxime Lalonde, Manuel Trauner, Anna Chanou, Matthias Weiβ, Clare S K Lee, Andreas Ettinger, Florian Erhard, Stefanie M Hauck, Stephan Hamperl","doi":"10.1038/s44319-025-00550-1","DOIUrl":"10.1038/s44319-025-00550-1","url":null,"abstract":"The CGG triplet repeat binding protein 1 (CGGBP1) binds to CGG repeats and has several important cellular functions, but how this DNA sequence-specific binding factor affects transcription and replication processes is an open question. Here, we show that CGGBP1 binds human gene promoters containing short (< 5) CGG-repeat tracts prone to R-loop formation. Loss of CGGBP1 leads to deregulated transcription, transcription-replication-conflicts (TRCs) and accumulation of Serine-5 phosphorylated RNA polymerase II (RNAPII), indicative of promoter-proximal stalling and a defect in transcription elongation. Consistently, an episomal CGG-repeat-containing model locus as well as endogenous genes show deregulated transcription, R-loop accumulation and increased RNAPII chromatin occupancy in CGGBP1-depleted cells. We identify the DEAD-box RNA:DNA helicases DDX41 and DHX15 as interaction partners specifically recruited by CGGBP1. Co-depletion experiments show that DDX41 and CGGBP1 work in the same pathway to unwind R-loops and avoid TRCs. Together, our work shows that short trinucleotide repeats are a source of genome-destabilizing secondary structures, and cells rely on specific DNA-binding factors to maintain proper transcription and replication coordination at short CGG repeats.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4691-4722"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947028","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}

引用次数: 0

p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma. p300/CBP是Ewing肉瘤致病性增强子活性和基因表达的重要驱动因子。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-01 Epub Date: 2025-09-01 DOI: 10.1038/s44319-025-00552-z

Laura C Godfrey, Brandon Regalado, Sydney R Schweber, Charles Hatton, Daniela V Wenge, Yanhe Wen, Meaghan Boileau, Maria Wessels, Jun Qi, Christopher J Ott, Kimberly Stegmaier, Miguel N Rivera, Scott A Armstrong

{"title":"p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma.","authors":"Laura C Godfrey, Brandon Regalado, Sydney R Schweber, Charles Hatton, Daniela V Wenge, Yanhe Wen, Meaghan Boileau, Maria Wessels, Jun Qi, Christopher J Ott, Kimberly Stegmaier, Miguel N Rivera, Scott A Armstrong","doi":"10.1038/s44319-025-00552-z","DOIUrl":"10.1038/s44319-025-00552-z","url":null,"abstract":"The t(11;22) translocation encodes the EWS::FLI1 fusion oncoprotein which is the primary driver of Ewing sarcoma. EWS::FLI1 creates unique, de novo pathogenic enhancers that drive gene expression and are a central mechanism of oncogenesis. Which chromatin regulatory proteins are critical to this mechanism is understudied. Here, we perform a comparative analysis of the function of the chromatin complexes MLL3/4 and p300/CBP in EWS::FLI1-mediated gene regulation. Using EWS::FLI1 degradation models, we define a subset of EWS::FLI1-sensitive enhancers whose activity correlates with p300/CBP function. We perturb both chromatin complexes to establish that in contrast to MLL3/4, p300/CBP is a critical regulator of EWS::FLI1-driven enhancer activity and downstream gene expression. We also show that p300/CBP small-molecule inhibition decelerates tumor growth in vivo. Our work highlights the context-dependent nature of chromatin protein activity at oncogenic enhancers and reveals p300/CBP as an important regulator of Ewing sarcoma.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4766-4793"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947061","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}

引用次数: 0

Structural obstruction to full DNA replication in terminally differentiated skeletal muscle cells. 末梢分化骨骼肌细胞DNA完全复制的结构性障碍。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-10-01 Epub Date: 2025-08-26 DOI: 10.1038/s44319-025-00554-x

Sara Zribi, Gladio Joel Giannitelli, Laura Bernardini, Federica Censi, Serena Camerini, Lucia Bertuccini, Francesca Iosi, Emilia Giannella, Massimo Sanchez, Elisa Consoli, Andrea Casagrande, Alessandra Cenci, Giovanna Floridia, Antonio Novelli, Alessandro Giuliani, Vincenzo Costanzo, Marco Crescenzi, Deborah Pajalunga

{"title":"Structural obstruction to full DNA replication in terminally differentiated skeletal muscle cells.","authors":"Sara Zribi, Gladio Joel Giannitelli, Laura Bernardini, Federica Censi, Serena Camerini, Lucia Bertuccini, Francesca Iosi, Emilia Giannella, Massimo Sanchez, Elisa Consoli, Andrea Casagrande, Alessandra Cenci, Giovanna Floridia, Antonio Novelli, Alessandro Giuliani, Vincenzo Costanzo, Marco Crescenzi, Deborah Pajalunga","doi":"10.1038/s44319-025-00554-x","DOIUrl":"10.1038/s44319-025-00554-x","url":null,"abstract":"Terminal cell differentiation is often associated with permanent withdrawal from proliferation, termed the postmitotic state. Though widespread among vertebrates and determinant for their biology, the molecular underpinnings of this state are poorly understood. Postmitotic skeletal muscle myotubes can be induced to reenter the cell cycle; however, they generally die as a result of their inability to complete DNA replication. Here, we explore the causes of such incompetence. Genomic hybridization of newly synthesized DNA shows that the replicative failure does not concern specific genomic regions, but can stochastically affect any of them. Myoblast and myotube nuclei are incubated in replicative Xenopus egg extract, which provides a full DNA replication machinery. While myoblast nuclei attain complete DNA replication, those from myotubes, even in these conditions, duplicate less than half of their genomes, strongly indicating that the structure of myotube chromatin obstructs DNA replication. Furthermore, disassembling and disorganizing chromatin with a strong salt treatment does not modify the replicative differences between the two types of nuclei, suggesting that they are rooted in the core structure of chromatin.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4633-4655"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947073","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}

引用次数: 0