EMBO Reports最新文献

PCAF-mediated acetylation regulates RAD51 dynamic localization on chromatin during HR repair. 在HR修复过程中，pcaf介导的乙酰化调节RAD51在染色质上的动态定位。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-15 DOI: 10.1038/s44319-025-00513-6

Jiajia Hou, Munan Shi, Jialu Hong, Yuting Liu, Xinyi Song, Haipeng Rao, Ying Ma, Chunchun Huang, Zhigang Hu, Lingfeng He, Zhigang Guo, Feiyan Pan

{"title":"PCAF-mediated acetylation regulates RAD51 dynamic localization on chromatin during HR repair.","authors":"Jiajia Hou, Munan Shi, Jialu Hong, Yuting Liu, Xinyi Song, Haipeng Rao, Ying Ma, Chunchun Huang, Zhigang Hu, Lingfeng He, Zhigang Guo, Feiyan Pan","doi":"10.1038/s44319-025-00513-6","DOIUrl":"https://doi.org/10.1038/s44319-025-00513-6","url":null,"abstract":"PCAF (p300-associated factor), a major histone acetyltransferase, is involved in many metabolic and pathogenic diseases. Here, we reveal a novel function of PCAF in homologous recombination repair (HR). We demonstrate that RAD51, a core protein in HR repair, physically interacts with the acetyltransferase domain of PCAF and is acetylated at lysine 40. This acetylation promotes RAD51 binding to ubiquitin, leading to its degradation via the ubiquitin-proteasome pathway. Following etoposide treatment, PCAF-induced acetylation removes RAD51 from chromatin to facilitate the late-phase HR processes. Overexpression of PCAF promotes premature dissociation of RAD51 from DNA damage sites. Notably, PCAF is downregulated in many cancers compared to adjacent tissues, correlating with shortened patient survival. Our findings suggest that decreased PCAF expression enhances HR efficiency, contributing to drug resistance in tumor cells, and the impact of PCAF on HR is dependent on its acetyltransferase activity. Our results highlight a novel role of PCAF in HR and provide a possible mechanism for tumor development and drug resistance caused by low expression of PCAF.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642097","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 pivot-tether model for nucleosome recognition by the chromosomal passenger complex. 染色体乘客复合体识别核小体的枢轴-系绳模型。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-15 DOI: 10.1038/s44319-025-00523-4

Reinis R Ruza, Chyi Wei Chung, Danny B H Gold, Michela Serena, Emile Roberts, Ulrike Gruneberg, Francis A Barr

{"title":"A pivot-tether model for nucleosome recognition by the chromosomal passenger complex.","authors":"Reinis R Ruza, Chyi Wei Chung, Danny B H Gold, Michela Serena, Emile Roberts, Ulrike Gruneberg, Francis A Barr","doi":"10.1038/s44319-025-00523-4","DOIUrl":"https://doi.org/10.1038/s44319-025-00523-4","url":null,"abstract":"Spatial restriction of Aurora B to T3-phosphorylated histone H3 (H3pT3) nucleosomes adjacent to centromeres during prometaphase and metaphase enables it to phosphorylate proteins necessary for spindle assembly checkpoint signalling and biorientation of chromosomes on the mitotic spindle. Aurora B binding to H3pT3-nucleosomes requires a multivalent targeting module, the chromosomal passenger complex (CPC), consisting of survivin, borealin, and INCENP. To shed light on how these components mediate CPC localisation during prometaphase and metaphase, we determined the structure of the CPC targeting module in complex with haspin-phosphorylated H3pT3-nucleosomes by cryo-electron microscopy. This structure shows how the N-terminus of borealin and the survivin BIR domain act as pivot and flexible tethering points, respectively, to increase CPC affinity for H3pT3 nucleosomes without limiting it to a specific orientation. We demonstrate that this flexible, yet constrained pivot-tether arrangement is important for the control of spindle assembly checkpoint signalling by Aurora B.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642095","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

Modular architecture of K⁺ channels: the functional plasticity of the pore module. K+通道的模块化结构：孔隙模块的功能可塑性。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-15 DOI: 10.1038/s44319-025-00519-0

Oliver Rauh, Tobias Schulze, James L Van Etten, Gerhard Thiel, Anna Moroni

{"title":"Modular architecture of K+ channels: the functional plasticity of the pore module.","authors":"Oliver Rauh, Tobias Schulze, James L Van Etten, Gerhard Thiel, Anna Moroni","doi":"10.1038/s44319-025-00519-0","DOIUrl":"https://doi.org/10.1038/s44319-025-00519-0","url":null,"abstract":"Miniature K+ channel proteins from viruses (Kcv) are structurally and functionally equivalent to the pore module of all K+ channels. Here, we summarize data in support of the hypothesis that pores of primitive K+ channels served as building blocks for evolving the modern complex mammalian ion channels. Experimental data show that mutations in Kcv channels can generate gating phenomena like slow-activating inward or outward rectification, which are typical of complex mammalian channels. Hence, the basic mechanism for rectification is an inherent property of the pore module, which was further tuned and/or amplified during evolution by the addition of sensory protein domains. This evolutionary trend can be experimentally mimicked by coupling small pore units with a voltage-sensing domain or a glutamate-binding domain to acquire voltage and ligand-sensitive gating. The same modularity principle can be exploited in the design of synthetic channels in which the Kcv pore is coupled to orthogonal sensor domains. These synthetic channels exhibit new gating properties like a sensitivity to light or Ca2+, which originate from their attached sensor domains.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642096","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

Machines like us scientists? : AI tools for mining the scientific literature in basic biomedical science. 像我们科学家一样的机器？：用于基础生物医学科学科学文献挖掘的AI工具。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-10 DOI: 10.1038/s44319-025-00522-5

Blanche Schwappach

引用次数: 0

Growth phase diets diminish histone acetyltransferase Gcn5 function and shorten lifespan of Drosophila males. 生长期饮食降低组蛋白乙酰转移酶Gcn5功能，缩短雄性果蝇寿命。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-10 DOI: 10.1038/s44319-025-00503-8

Shoko Mizutani, Kanji Furuya, Ayumi Mure, Yuuki Takahashi, Akihiro Mori, Nozomu Sakurai, Takuto Suito, Kohjiro Nagao, Masato Umeda, Kaori Watanabe, Yukako Hattori, Tadashi Uemura

{"title":"Growth phase diets diminish histone acetyltransferase Gcn5 function and shorten lifespan of Drosophila males.","authors":"Shoko Mizutani, Kanji Furuya, Ayumi Mure, Yuuki Takahashi, Akihiro Mori, Nozomu Sakurai, Takuto Suito, Kohjiro Nagao, Masato Umeda, Kaori Watanabe, Yukako Hattori, Tadashi Uemura","doi":"10.1038/s44319-025-00503-8","DOIUrl":"https://doi.org/10.1038/s44319-025-00503-8","url":null,"abstract":"The nutritional environment in early life, referred to as the nutrition history, exerts far-reaching health effects beyond the developmental stage. Here, with Drosophila melanogaster as a model, we fed larvae on diets consisting of a variety of yeast mutants and explored the resulting histories that impacted adult lifespan. A larval diet comprised of yeast nat3 KO shortened the lifespan of male adults; and remarkably, this diet diminished the function of histone acetyltransferase Gcn5 in larvae. Concordantly, perturbation of Gcn5-mediated gene regulation in the larval whole body or neurons significantly contributed to the earlier death of adults. The nat3 KO diet is much more abundant in long-chain fatty acids and branched-chain amino acids (BCAAs) than the control yeast diet. Supplementing the control diet with a combination of oleic acid, valine, and acetic acid recapitulated the effects of the nat3 KO diet on the larval transcriptome and the lifespan of males. Our findings strongly suggest a causal link between a fatty acids- and BCAA-rich diet in developmental stages and lifespan reduction via the adverse effect on the Gcn5 function.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607852","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 genetic framework for RNAi inheritance in Caenorhabditis elegans. 秀丽隐杆线虫RNAi遗传的遗传框架。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-07 DOI: 10.1038/s44319-025-00512-7

Jan Schreier, Lizaveta Pshanichnaya, Fridolin Kielisch, René F Ketting

{"title":"A genetic framework for RNAi inheritance in Caenorhabditis elegans.","authors":"Jan Schreier, Lizaveta Pshanichnaya, Fridolin Kielisch, René F Ketting","doi":"10.1038/s44319-025-00512-7","DOIUrl":"https://doi.org/10.1038/s44319-025-00512-7","url":null,"abstract":"Gene regulation by RNA interference (RNAi) is a conserved process driven by double-stranded RNA (dsRNA). It responds to exogenous cues and drives endogenous gene regulation. In Caenorhabditis elegans, RNAi can be inherited from parents to offspring. While a number of factors have been implicated in this inheritance process, we do not understand how and when they function. Using a new inheritance assay, we establish a hierarchy amongst previously identified inheritance factors. We show that the nuclear Argonaute protein HRDE-1 is required for RNAi establishment in parents and offspring, but not for the inheritance process. In contrast, the cytoplasmic Argonaute protein WAGO-3 is the only factor essential for inheritance, via sperm and oocyte, while not affecting establishment in either parent or offspring. We propose a cycle in which nuclear and cytoplasmic Argonaute proteins interact to generate both a silencing response and a cytoplasmic factor that transmits the silencing between parent and offspring, WAGO-3. Finally, we implicate the RNA helicase ZNFX-1 as a factor that allows the inherited WAGO-3 protein to trigger silencing in the offspring.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583382","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

Inhibition of the minor spliceosome restricts the growth of a broad spectrum of cancers. 对小剪接体的抑制限制了多种癌症的生长。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-07 DOI: 10.1038/s44319-025-00511-8

Karen Doggett, Kimberly J Morgan, Anouk M Olthof, Stephen Mieruszynski, Benjamin B Williams, Alexandra L Garnham, Michael J G Milevskiy, Lachlan Whitehead, Janine Coates, Michael Buchert, Robert J J O'Donoghue, Thomas E Hall, Tracy L Putoczki, Matthias Ernst, Kate D Sutherland, Rahul N Kanadia, Joan K Heath

{"title":"Inhibition of the minor spliceosome restricts the growth of a broad spectrum of cancers.","authors":"Karen Doggett, Kimberly J Morgan, Anouk M Olthof, Stephen Mieruszynski, Benjamin B Williams, Alexandra L Garnham, Michael J G Milevskiy, Lachlan Whitehead, Janine Coates, Michael Buchert, Robert J J O'Donoghue, Thomas E Hall, Tracy L Putoczki, Matthias Ernst, Kate D Sutherland, Rahul N Kanadia, Joan K Heath","doi":"10.1038/s44319-025-00511-8","DOIUrl":"https://doi.org/10.1038/s44319-025-00511-8","url":null,"abstract":"Minor splicing is an under-appreciated splicing system required for the correct expression of ~700 genes in the human genome. This small subset of genes (0.35%) harbours introns containing non-canonical splicing sequences that are recognised uniquely by the minor spliceosome and cannot be processed by the major spliceosome. Using in vivo zebrafish and mouse cancer models, we show that heterozygous expression of Rnpc3, encoding a unique protein component of the minor spliceosome, restricts the growth and survival of liver, lung and gastric tumours without impacting healthy cells. RNPC3 knockdown in human lung cancer-derived A549 cells also impairs cell proliferation and RNA-seq analysis reveals a robust and selective disruption to minor intron splicing and transcription-wide effects on gene expression. We further demonstrate that these perturbations are accompanied by DNA replication stress, DNA damage, accumulation of TP53 protein and activation of a Tp53-dependent transcriptional program that induces cell cycle arrest and apoptosis. Together our data reveal a vulnerability of cancer cells to minor splicing inhibition that restricts tumour growth.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583383","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

Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer. Hippo通路控制生物蝶呤代谢以保护肺癌中邻近细胞免于铁下垂。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-07 DOI: 10.1038/s44319-025-00515-4

Hao Li, Yohei Kanamori, Akihiro Nita, Ayato Maeda, Tianli Zhang, Kenta Kikuchi, Hiroyuki Yamada, Touya Toyomoto, Mohamed Fathi Saleh, Mayumi Niimura, Hironori Hinokuma, Mayuko Shimoda, Koei Ikeda, Makoto Suzuki, Yoshihiro Komohara, Daisuke Kurotaki, Tomohiro Sawa, Toshiro Moroishi

{"title":"Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer.","authors":"Hao Li, Yohei Kanamori, Akihiro Nita, Ayato Maeda, Tianli Zhang, Kenta Kikuchi, Hiroyuki Yamada, Touya Toyomoto, Mohamed Fathi Saleh, Mayumi Niimura, Hironori Hinokuma, Mayuko Shimoda, Koei Ikeda, Makoto Suzuki, Yoshihiro Komohara, Daisuke Kurotaki, Tomohiro Sawa, Toshiro Moroishi","doi":"10.1038/s44319-025-00515-4","DOIUrl":"https://doi.org/10.1038/s44319-025-00515-4","url":null,"abstract":"Recent advances in single-cell technologies have uncovered significant cellular diversity in tumors, influencing cancer progression and treatment outcomes. The Hippo pathway controls cell proliferation through its downstream effectors: yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Our analysis of human lung adenocarcinoma and murine models revealed that cancer cells display heterogeneous YAP/TAZ activation levels within tumors. Murine lung cancer cells with high YAP/TAZ activity grow rapidly but are sensitive to ferroptosis, a cell death induced by lipid peroxidation. In contrast, cells with low YAP/TAZ activity grow slowly but resist ferroptosis. Moreover, they protect neighbouring cells from ferroptosis, creating a protective microenvironment that enhances the tumor's resistance to ferroptosis. Mechanistically, inhibiting YAP/TAZ upregulates GTP cyclohydrolase 1 (GCH1), an enzyme critical for the biosynthesis of tetrahydrobiopterin (BH4), which functions as a secretory antioxidant to prevent lipid peroxidation. Pharmacological inhibition of GCH1 sensitizes lung cancer cells to ferroptosis inducers, suggesting a potential therapeutic approach. Our data highlights the non-cell-autonomous roles of the Hippo pathway in creating a ferroptosis-resistant tumor microenvironment.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575075","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

Molecular mechanisms of co-infections. 共感染的分子机制。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-04 DOI: 10.1038/s44319-025-00517-2

Philipp Darius Konstantin Walch, Petr Broz

{"title":"Molecular mechanisms of co-infections.","authors":"Philipp Darius Konstantin Walch, Petr Broz","doi":"10.1038/s44319-025-00517-2","DOIUrl":"https://doi.org/10.1038/s44319-025-00517-2","url":null,"abstract":"Co-infections generally cause exacerbated pathologies in patients, yet a knowledge gap between clinical data and the underlying molecular mechanisms remains. Clinical studies focus on patient outcome, but much less is known about molecular mechanisms and convergence points that define the interaction between different pathogens. In this review, we will summarize the current standing of the literature at the various scales of magnitude that co-infections impact: epidemiology, clinical observations, tissue- and organ-specificity, the single-cell level, and molecular mechanisms. Given the scarcity of systematic research across systems, we will focus on molecular interaction points that have been identified, comment on their generalizability and, where required, extrapolate from single-pathogen studies. More research of the host-pathogen-pathogen interface is direly warranted, and we hope to inspire advances addressing the intricate network between two co-occurring pathogens and their host. In addition to direct implications for co-infections, acquiring a better understanding of how microorganisms interact in this complex environment will enable us to better understand single-pathogen infections as well, which can lead to the development of novel treatment approaches.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564693","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

Oncogenic YAP sensitizes cells to CHK1 inhibition via CDK4/6 driven G1 acceleration. 致癌YAP通过CDK4/6驱动的G1加速使细胞对CHK1抑制敏感。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-04 DOI: 10.1038/s44319-025-00514-5

Dörthe Gertzmann, Cornelius Presek, Anna Lena Mattes, Marco Sänger, Marie Zoller, Christina Schülein-Völk, Carsten P Ade, Martin Eilers, Stefan Gaubatz

{"title":"Oncogenic YAP sensitizes cells to CHK1 inhibition via CDK4/6 driven G1 acceleration.","authors":"Dörthe Gertzmann, Cornelius Presek, Anna Lena Mattes, Marco Sänger, Marie Zoller, Christina Schülein-Völk, Carsten P Ade, Martin Eilers, Stefan Gaubatz","doi":"10.1038/s44319-025-00514-5","DOIUrl":"https://doi.org/10.1038/s44319-025-00514-5","url":null,"abstract":"Replication stress is a driver of genomic instability, contributing to carcinogenesis by causing DNA damage and mutations. While YAP, the downstream co-activator of the Hippo signaling pathway, plays a crucial role in regulating cell growth and differentiation, it is unclear whether it generates replication stress exploitable for therapy. Here, we report that oncogenic YAP shortens the G1 phase through increased CDK4/6 activity, leading to early S-phase entry. This causes origin underlicensing, an overall reduced rate of DNA replication, and, unusually, an accelerated speed of individual replication forks. CHK1 inhibition in cells expressing oncogenic YAP results in DNA damage during S-phase, which is not due to premature CDK1 activation or mitotic entry. Sensitivity to CHK1 inhibition depends on the YAP-TEAD interaction and involves a global increase in transcription and an increase in transcription-replication conflicts (TRCs). Replication stress from oncogenic YAP can be mitigated by restoring G1 length through partial CDK4/6 inhibition or by reducing YAP-induced hypertranscription. Our findings suggest a potential therapeutic strategy for targeting YAP-dependent cancers by exploiting their vulnerability to replication stress.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564695","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