EMBO Reports最新文献_第8页

Transcriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution. 转录组解码异常剪接在黑色素瘤mapk靶向抗性进化中的作用。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub Date: 2025-07-18 DOI: 10.1038/s44319-025-00521-6

Jing Yu, Xiujing He, Xueyan Wang, Chune Yu, Xian Jiang, Yanna Li, Xinyu Liu, Ya Luo, Xuemei Chen, Sisi Wu, Lu Si, Jing Jing, Xuelei Ma, Hubing Shi

{"title":"Transcriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution.","authors":"Jing Yu, Xiujing He, Xueyan Wang, Chune Yu, Xian Jiang, Yanna Li, Xinyu Liu, Ya Luo, Xuemei Chen, Sisi Wu, Lu Si, Jing Jing, Xuelei Ma, Hubing Shi","doi":"10.1038/s44319-025-00521-6","DOIUrl":"10.1038/s44319-025-00521-6","url":null,"abstract":"Drug resistance critically limits the long-term efficacy of MAPK-targeted therapy in melanoma. While resistance mechanisms at genetic, epigenetic, and transcriptional scales are well-documented, post-transcriptional splicing regulation remains poorly understood. By analyzing patient-matched pre-treatment and resistant melanoma biopsies, we uncover widespread alternative splicing alterations during therapy resistance. Splicing perturbations are most pronounced in MAPK and PI3K-AKT pathway genes. We identify a splicing switch of AKT2 from isoform 210 to 206 in 29.55% (13/44) of disease-progressive biopsies. This splicing switch induces AKT2 kinase hyperactivity by restoring the activated fragment A-loop. Functional validations confirm that AKT2-206 confers BRAF inhibitor resistance in melanoma cells by activating S6 kinase. Further, the splicing factor hnRNPK likely drives the splicing switch of AKT2 during acquired resistance. Our results not only provide insights into splicing-mediated regulation of drug resistance but also highlight the importance of alternative splicing isoforms as targets for clinical diagnosis and therapy.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4180-4196"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667416","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

Too much charity? 施舍太多？

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub Date: 2025-07-29 DOI: 10.1038/s44319-025-00542-1

Frank Gannon

引用次数: 0

Fool's-gold science : The ethical and scientific perils of testing most vaccines using placebo-controlled randomized trials. 傻瓜黄金科学：使用安慰剂对照随机试验测试大多数疫苗的伦理和科学风险。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub Date: 2025-07-31 DOI: 10.1038/s44319-025-00530-5

Arthur Caplan, Felicia L Pasadyn, Nathaniel Mamo

引用次数: 0

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

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub 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":"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":"3714-3729"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332146/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

JMJD3-mediated senescence is required to overcome stress-induced hematopoietic defects. jmjd3介导的衰老是克服应激诱导的造血缺陷所必需的。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub Date: 2025-06-25 DOI: 10.1038/s44319-025-00502-9

Yuichiro Nakata, Takeshi Ueda, Yasuyuki Sera, Miho Koizumi, Katsutoshi Imamura, Akinori Kanai, Ken-Ichiro Ikeda, Norimasa Yamasaki, Akiko Nagamachi, Kohei Kobatake, Masataka Taguchi, Yusuke Sotomaru, Tatsuo Ichinohe, Zen-Ichiro Honda, Takuro Nakamura, Ichiro Manabe, Toshio Suda, Keiyo Takubo, Osamu Kaminuma, Hiroaki Honda

{"title":"JMJD3-mediated senescence is required to overcome stress-induced hematopoietic defects.","authors":"Yuichiro Nakata, Takeshi Ueda, Yasuyuki Sera, Miho Koizumi, Katsutoshi Imamura, Akinori Kanai, Ken-Ichiro Ikeda, Norimasa Yamasaki, Akiko Nagamachi, Kohei Kobatake, Masataka Taguchi, Yusuke Sotomaru, Tatsuo Ichinohe, Zen-Ichiro Honda, Takuro Nakamura, Ichiro Manabe, Toshio Suda, Keiyo Takubo, Osamu Kaminuma, Hiroaki Honda","doi":"10.1038/s44319-025-00502-9","DOIUrl":"10.1038/s44319-025-00502-9","url":null,"abstract":"Cellular senescence in stem cells compromises regenerative capacity, promotes chronic inflammation, and is implicated in aging. Hematopoietic stem and progenitor cells (HSPCs) are responsible for producing mature blood cells, however, how cellular senescence influences their function is largely unknown. Here, we show that JMJD3, a histone demethylase, activates cellular senescence by upregulating p16Ink4a in competition with Polycomb group proteins, and reprograms HSPC integrity to overcome hematopoietic defects induced by replicative and oncogenic stresses. Jmjd3 deficiency does not alter global H3K27me3 levels, indicating that JMJD3 epigenetically regulates specific and limited JMJD3 targets under stress. JMJD3 deficiency also impairs stem cell potential, proper cell cycle regulation, and WNT pathway activation in HSPCs under stress. These impaired phenotypes are rescued through exogenous and retroviral introduction of p16Ink4a. This JMJD3-p16INK4a axis in hematopoiesis is age-dependent and is distinct from cellular senescence. Treatment with a selective JMJD3 inhibitor attenuates leukemic potential during cellular senescence. Taken together, these results demonstrate that JMJD3-p16INK4a mediates cellular senescence and plays critical roles in the functional integrity of HSPCs under stress.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3831-3855"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12331899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144495217","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

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 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub 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":"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":"3937-3969"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332006/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LRBA deficiency impairs autophagy and contributes to enhanced antigen presentation and T-cell dysregulation. LRBA缺乏损害自噬，并有助于增强抗原呈递和t细胞失调。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub Date: 2025-06-23 DOI: 10.1038/s44319-025-00504-7

Elena Sindram, Marie-Celine Deau, Laure-Anne Ligeon, Pablo Sanchez-Martin, Sigrun Nestel, Sophie Jung, Stefanie Ruf, Pankaj Mishra, Michele Proietti, Stefan Günther, Kathrin Thedieck, Eleni Roussa, Angelika Rambold, Christian Münz, Claudine Kraft, Bodo Grimbacher, Laura Gámez-Díaz

{"title":"LRBA deficiency impairs autophagy and contributes to enhanced antigen presentation and T-cell dysregulation.","authors":"Elena Sindram, Marie-Celine Deau, Laure-Anne Ligeon, Pablo Sanchez-Martin, Sigrun Nestel, Sophie Jung, Stefanie Ruf, Pankaj Mishra, Michele Proietti, Stefan Günther, Kathrin Thedieck, Eleni Roussa, Angelika Rambold, Christian Münz, Claudine Kraft, Bodo Grimbacher, Laura Gámez-Díaz","doi":"10.1038/s44319-025-00504-7","DOIUrl":"10.1038/s44319-025-00504-7","url":null,"abstract":"Reduced autophagy is associated with the aberrant humoral response observed in lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency; however, the molecular mechanisms and their impact on T-cell responses remain poorly understood. We identify two novel LRBA interactors, phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4) and FYVE And Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1), which each play key roles in autophagy. PIK3R4 facilitates the production of phosphatidylinositol-3 phosphate (PI(3)P) that promotes autophagosome formation and autophagosome-lysosome fusion, whereas FYCO1 supports autophagosome movement. LRBA-knockout (KO) cells show impaired PI(3)P production, reduced autophagosome-lysosome fusion, accumulation of enlarged autophagosomes, and decreased cargo degradation. In line with the role of autophagy as a major degradation system for MHC-II loading and antigen presentation, we observe increased numbers of MHC class II and LC3 vesicles, along with enhanced antigen presentation in absence of LRBA, resulting in a higher production of proinflammatory cytokines from T cells in vitro. Our work suggests a novel biological role of LRBA controlling antigen presentation and T-cell responses by positively regulating autophagy, which may contribute to T-cell immune dysregulation observed in LRBA-deficient patients.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4040-4071"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474323","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

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 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub 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":"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":"4017-4039"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373906/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CLIPPERs - Clip the right protein - a new tool for targeted proteolysis in bacteria. CLIPPERs -夹住正确的蛋白质-细菌中靶向蛋白水解的新工具。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub Date: 2025-07-25 DOI: 10.1038/s44319-025-00532-3

Marta Carroni

引用次数: 0

BRCA1 preserves genome integrity during the formation of undifferentiated spermatogonia. BRCA1在未分化精原细胞形成过程中保持了基因组的完整性。

IF 6.2 1区生物学

EMBO Reports Pub Date : 2025-08-01 Epub Date: 2025-05-28 DOI: 10.1038/s44319-025-00487-5

Peng Li, Licun Song, Longfei Ma, Chunsheng Han, Lejun Li, Lin-Yu Lu, Yidan Liu

{"title":"BRCA1 preserves genome integrity during the formation of undifferentiated spermatogonia.","authors":"Peng Li, Licun Song, Longfei Ma, Chunsheng Han, Lejun Li, Lin-Yu Lu, Yidan Liu","doi":"10.1038/s44319-025-00487-5","DOIUrl":"10.1038/s44319-025-00487-5","url":null,"abstract":"Undifferentiated spermatogonia, which form shortly after birth, consist of spermatogonial stem cells and progenitor spermatogonia that maintain homeostasis. As the origin of spermatogenesis, undifferentiated spermatogonia must preserve genome integrity. Paradoxically, we demonstrate that massive spontaneous DNA damage, potentially generated by formaldehyde, arises during the formation of undifferentiated spermatogonia, posing a significant threat to genome integrity. We further reveal that BRCA1 is essential for the timely repair of this spontaneous DNA damage. BRCA1 loss leads to a dramatic reduction in progenitor spermatogonia and disrupts the formation of undifferentiated spermatogonia. Although spermatogonial stem cells initially undergo hyperproliferation, they are eventually depleted, resulting in the premature exhaustion of undifferentiated spermatogonia. Our study highlights a striking difference in DNA damage sensitivity between the two populations of undifferentiated spermatogonia and underscores the critical role of BRCA1-dependent DNA damage repair in preserving genome integrity during the formation of undifferentiated spermatogonia.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3747-3772"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173316","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