EMBO Journal最新文献

ATXN3 regulates lysosome regeneration after damage by targeting K48-K63-branched ubiquitin chains. ATXN3通过靶向k48 - k63分支泛素链调控损伤后溶酶体再生。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-07-29 DOI: 10.1038/s44318-025-00517-x

Maike Reinders, Bojana Kravic, Pinki Gahlot, Sandra Koska, Johannes van den Boom, Nina Schulze, Sophie Levantovsky, Stefan Kleine, Markus Kaiser, Yogesh Kulathu, Christian Behrends, Hemmo Meyer

{"title":"ATXN3 regulates lysosome regeneration after damage by targeting K48-K63-branched ubiquitin chains.","authors":"Maike Reinders, Bojana Kravic, Pinki Gahlot, Sandra Koska, Johannes van den Boom, Nina Schulze, Sophie Levantovsky, Stefan Kleine, Markus Kaiser, Yogesh Kulathu, Christian Behrends, Hemmo Meyer","doi":"10.1038/s44318-025-00517-x","DOIUrl":"https://doi.org/10.1038/s44318-025-00517-x","url":null,"abstract":"The cellular response to lysosomal damage involves fine-tuned mechanisms of membrane repair, lysosome regeneration and lysophagy, but how these different processes are coordinated is unclear. Here we show in human cells that the deubiquitinating enzyme ATXN3 helps restore integrity of the lysosomal system after damage by targeting K48-K63-branched ubiquitin chains on regenerating lysosomes. We find that ATXN3 is required for lysophagic flux after lysosomal damage but is not involved in the initial phagophore formation on terminally damaged lysosomes. Instead, ATXN3 is recruited to a distinct subset of lysosomes that are decorated with phosphatidylinositol-(4,5)-bisphosphate and that are not yet fully reacidified. There, ATXN3, along with its partner VCP/p97, targets and turns over K48-K63-branched ubiquitin conjugates. ATXN3 thus facilitates degradation of a fraction of LAMP2 via microautophagy to regenerate the lysosomal membrane and to thereby reestablish degradative capacity needed also for completion of lysophagy. Our findings identify a key role of ATXN3 in restoring lysosomal function after lysosomal membrane damage and uncover K48-K63-branched ubiquitin chain-regulated regeneration as a critical element of the lysosomal damage stress response.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144745796","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

YTHDF3 recognizes DNA N6-methyladenine and recruits ALKBH1 for 6mA removal from genomic DNA. YTHDF3识别DNA n6 -甲基腺嘌呤并招募ALKBH1从基因组DNA中去除6mA。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-07-25 DOI: 10.1038/s44318-025-00512-2

Xin-Hui Chen, Zi-Lu Wang, Jincui Yang, Min Chen, Si-Yi Zhao, Kun-Xiong Guo, Xuelong Zheng, Zhengwei Zhao, Xiaoqiang Chen, Jing Li, Min-Min Zhang, Ling Ran, Huifang Zhu, Xiao-Feng Gu, Guang-Rong Yan

{"title":"YTHDF3 recognizes DNA N6-methyladenine and recruits ALKBH1 for 6mA removal from genomic DNA.","authors":"Xin-Hui Chen, Zi-Lu Wang, Jincui Yang, Min Chen, Si-Yi Zhao, Kun-Xiong Guo, Xuelong Zheng, Zhengwei Zhao, Xiaoqiang Chen, Jing Li, Min-Min Zhang, Ling Ran, Huifang Zhu, Xiao-Feng Gu, Guang-Rong Yan","doi":"10.1038/s44318-025-00512-2","DOIUrl":"https://doi.org/10.1038/s44318-025-00512-2","url":null,"abstract":"DNA N6-methyladenine (6mA) is an emerging epigenetic mark in the mammalian genome. ALKBH1 preferentially exhibits 6mA demethylase activity for single-stranded DNA (ssDNA) or bubbled/bulged DNA, but not for double-stranded DNA (dsDNA). Nevertheless, ALKBH1 significantly decreases the cellular 6mA level in genomic DNA, whose prevailing DNA conformation in living mammalian cells is dsDNA. Therefore, the demethylase activity of ALKBH1 toward 6mA in genomic DNA, especially dsDNA, remains largely debated. Here, we found that YTHDF3 increases the 6mA demethylase activity of ALKBH1 in genomic DNA with different conformations, including dsDNA. Compared with ALKBH1, YTHDF3 preferentially recognizes and binds to 6mA-modified DNA with different conformations. YTHDF3 recognizes 6mA in genomic DNA, and binds ALKBH1 to recruit it to sites near 6mA in genomic DNA, thereby facilitating the ALKBH1-mediated removal of 6mA in genomic dsDNA. In summary, YTHDF3 is a novel genomic DNA reader and guides ALKBH1 to remove 6mA in human genomic DNA.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719015","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

Master transcription-factor binding sites constitute the core of early replication control elements. 主转录因子结合位点构成早期复制控制元件的核心。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-07-17 DOI: 10.1038/s44318-025-00501-5

Jesse L Turner, Laura Hinojosa-Gonzalez, Takayo Sasaki, Satoshi Uchino, Athanasios Vouzas, Mariella S Soto, Abhijit Chakraborty, Karen E Alexander, Cheryl A Fitch, Amber N Brown, Ferhat Ay, David M Gilbert

{"title":"Master transcription-factor binding sites constitute the core of early replication control elements.","authors":"Jesse L Turner, Laura Hinojosa-Gonzalez, Takayo Sasaki, Satoshi Uchino, Athanasios Vouzas, Mariella S Soto, Abhijit Chakraborty, Karen E Alexander, Cheryl A Fitch, Amber N Brown, Ferhat Ay, David M Gilbert","doi":"10.1038/s44318-025-00501-5","DOIUrl":"10.1038/s44318-025-00501-5","url":null,"abstract":"Eukaryotic genomes replicate in a defined temporal order called the replication timing (RT) program. RT is developmentally regulated with the potential to drive cell fate transitions, but mechanisms controlling RT remain elusive. We previously identified \"Early Replication Control Elements\" (ERCEs), cis-acting elements necessary for early RT, domain-wide transcription, 3D chromatin architecture and compartmentalization in mouse embryonic stem cells (mESCs), but deletions identifying ERCEs were large and encompassed many putative regulatory elements. Here, we show that ERCEs are compound elements, whose RT activity can largely be accounted for by multiple binding sites for diverse master transcription factors (subERCEs). While deletion of subERCEs had large effects on both transcription and replication timing, deleting transcription start sites eliminated nearly all transcription with only moderate effects on replication timing. Our results suggest a model in which subERCEs are a class of transcriptional enhancers that can also organize chromatin domains structurally to support early replication timing, potentially providing a feed-forward loop to drive robust epigenomic change during cell fate transitions.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660958","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 proteostatic landscape of healthy human oocytes. 健康人类卵母细胞的蛋白酶抑制景观。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-07-16 DOI: 10.1038/s44318-025-00493-2

Gabriele Zaffagnini, Miquel Solé, Juan Manuel Duran, Nikolaos P Polyzos, Elvan Böke

{"title":"The proteostatic landscape of healthy human oocytes.","authors":"Gabriele Zaffagnini, Miquel Solé, Juan Manuel Duran, Nikolaos P Polyzos, Elvan Böke","doi":"10.1038/s44318-025-00493-2","DOIUrl":"https://doi.org/10.1038/s44318-025-00493-2","url":null,"abstract":"Oocytes, female germ cells that develop into eggs, are among the longest-lived cells in the animal body. Recent studies on mouse oocytes highlight unique adaptations in protein homeostasis (proteostasis) within these cells. However, the mechanisms of proteostasis in human oocytes remain virtually unstudied. We present the first large-scale study of proteostatic activity in human oocytes using over 100 freshly donated oocytes from 21 healthy women aged 19-34 years. We analysed the activity and distribution of lysosomes, proteasomes, and mitochondria in both immature and mature oocytes. Notably, human oocytes exhibit nearly twofold lower proteolytic activity than surrounding somatic cells, with further decreases as oocytes mature. Oocyte maturation is also coupled with lysosomal exocytosis and a decrease in mitochondrial membrane potential. We propose that reduced organelle activity preserves key cellular components critical for early embryonic development during the prolonged maturation of human oocytes. Our findings highlight the distinctive biology of human oocytes and the need to investigate human-specific reproductive biology to address challenges in female fertility.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651116","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

Optochemical profiling of NMDAR molecular diversity at synaptic and extrasynaptic sites. 突触和突触外NMDAR分子多样性的光化学分析。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-07-08 DOI: 10.1038/s44318-025-00498-x

Antoine Sicard, Meilin Tian, Zakaria Mostefai, Sophie Shi, Cécile Cardoso, Joseph Zamith, Isabelle McCort-Tranchepain, Cécile Charrier, Pierre Paoletti, Laetitia Mony

{"title":"Optochemical profiling of NMDAR molecular diversity at synaptic and extrasynaptic sites.","authors":"Antoine Sicard, Meilin Tian, Zakaria Mostefai, Sophie Shi, Cécile Cardoso, Joseph Zamith, Isabelle McCort-Tranchepain, Cécile Charrier, Pierre Paoletti, Laetitia Mony","doi":"10.1038/s44318-025-00498-x","DOIUrl":"https://doi.org/10.1038/s44318-025-00498-x","url":null,"abstract":"Neurotransmitter receptors are critical for neuronal communication. They often form large multimeric complexes that differ in their subunit composition, distribution, and signaling properties. N-methyl-D-aspartate receptors (NMDARs), a class of glutamate-gated ion channels with essential roles in brain development and plasticity, co-exist as multiple subtypes, with GluN2A diheteromers, GluN2B diheteromers, and GluN2A/GluN2B triheteromers prevailing in the adult forebrain. Studying individual subtypes in native tissues with subunit stoichiometry resolution remains challenging, and the relative abundance and subcellular distribution of these subtypes remain controversial. Here we develop and use the photochemical tool Opto2B for specific and reversible modulation of GluN2B diheteromers, while leaving other receptor subtypes (in particular GluN2A/GluN2B triheteromers) unaffected. Using Opto2B, we characterize the differential contribution of GluN2B diheteromers to synaptic and extrasynaptic NMDAR pools during mouse development. Our results suggest that GluN2A receptors predominate in both pools in adult hippocampal CA1 pyramidal cells, with no preferential contribution of GluN2B diheteromers to extrasynaptic currents, challenging the common view that GluN2A and GluN2B NMDARs segregate in synaptic and extrasynaptic compartments, respectively. Our study addresses long-standing questions on extrasynaptic NMDARs and paves the way for interrogating NMDAR signaling diversity with unprecedented molecular and spatio-temporal resolution.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592851","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

TERRA R-loops trigger a switch in telomere maintenance towards break-induced replication and PRIMPOL-dependent repair. TERRA r -环触发端粒维护向断裂诱导复制和primpol依赖性修复的开关。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-07-07 DOI: 10.1038/s44318-025-00502-4

Suna In, Patricia Renck Nunes, Rita Valador Fernandes, Joachim Lingner

{"title":"TERRA R-loops trigger a switch in telomere maintenance towards break-induced replication and PRIMPOL-dependent repair.","authors":"Suna In, Patricia Renck Nunes, Rita Valador Fernandes, Joachim Lingner","doi":"10.1038/s44318-025-00502-4","DOIUrl":"https://doi.org/10.1038/s44318-025-00502-4","url":null,"abstract":"TERRA long noncoding RNAs associate with telomeres post transcription through base-pairing with telomeric DNA forming R-loop structures. TERRA regulates telomere maintenance but its exact modes of action remain unknown. Here, we induce TERRA transcription and R-loop formation in telomerase-expressing cells and determine that TERRA R-loop formation requires non-redundant functions of the RAD51 DNA recombinase and its enhancer RAD51AP1. TERRA R-loops interfere with semiconservative DNA replication, promoting telomere maintenance by a homology-directed repair (HDR) mechanism known as break-induced replication (BIR), which ensures telomere maintenance in ALT cancer cells. In addition, TERRA induces PRIMPOL-dependent repair, which can initiate DNA synthesis de novo downstream of replication obstacles. PRIMPOL acts in parallel to BIR for telomere maintenance of TERRA-overexpressing cells, promoting their survival. Similarly, we find that PRIMPOL depletion is synthetic-lethal with BIR deficiency in U2OS ALT cancer cells. Therefore, TERRA R-loops by themselves are sufficient to induce ALT-typical telomere repair mechanisms, in the absence of other ALT-typical telomeric chromatin changes.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585558","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 million shades of green: understanding and harnessing plant metabolic diversity. 一百万种绿色：理解和利用植物代谢多样性。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-07-03 DOI: 10.1038/s44318-025-00496-z

Rocky D Payet, Adnane Aouidate, Rebecca Casson, Alan Houghton, Mai-Truc Pham, Anne Osbourn

引用次数: 0

Super-resolution imaging of native fluorescent photoreceptors in chytrid fungal eyes. 壶菌眼内天然荧光光感受器的超分辨率成像。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-07-01 Epub Date: 2025-05-27 DOI: 10.1038/s44318-025-00452-x

Wayne Busse, Enrico Klotzsch, Yousef Yari Kamrani, Natalie Wordtmann, Simon Kelterborn, Peter Hegemann, Matthias Broser

{"title":"Super-resolution imaging of native fluorescent photoreceptors in chytrid fungal eyes.","authors":"Wayne Busse, Enrico Klotzsch, Yousef Yari Kamrani, Natalie Wordtmann, Simon Kelterborn, Peter Hegemann, Matthias Broser","doi":"10.1038/s44318-025-00452-x","DOIUrl":"10.1038/s44318-025-00452-x","url":null,"abstract":"Photoorientation in motile fungal zoospores is mediated by rhodopsin guanylyl cyclases (RGCs). In certain chytrids, these photoreceptors form heterodimers consisting of a visible-light-absorbing RGC paired with neorhodopsin (NeoR), a rhodopsin distinguished by its unique spectral properties: far-red absorption and high fluorescence. Leveraging the native fluorescence of NeoR, we detected RGCs in living zoospores of the fungus Rhizoclosmatium globosum. The reversible photoswitching of bistable NeoR enabled super-resolution microscopy, facilitating single-molecule detection and quantification of NeoR proteins within individual zoospores. This approach also revealed the precise localization of RGCs within the rumposome, a chytrid-specific organelle hypothesized to mediate photoreception. Fluorescence tracking across different stages of the chytrid life cycle and the analysis of transcriptomic data confirmed that RGCs are predominantly present during the zoospore stage. Functional assays of recombinantly expressed RGC heterodimers with modified substrate specificity revealed that only one of the two pseudo-symmetric nucleotide-binding sites is catalytically active. Strikingly, disrupting nucleotide binding in the non-catalytic site enhanced light-triggered cyclase activity by up to ninefold, indicating an allosteric regulatory mechanism in heterodimeric RGCs.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4088-4103"},"PeriodicalIF":9.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163468","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

Epigenetic regulation of neural stem cell aging in the mouse hippocampus by Setd8 downregulation. Setd8下调对小鼠海马神经干细胞衰老的表观遗传调控。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-07-01 Epub Date: 2025-06-03 DOI: 10.1038/s44318-025-00455-8

Shuzo Matsubara, Kanae Matsuda-Ito, Haruka Sekiryu, Hiroyoshi Doi, Takumi Nakagawa, Naoya Murao, Hisanobu Oda, Kinichi Nakashima, Taito Matsuda

{"title":"Epigenetic regulation of neural stem cell aging in the mouse hippocampus by Setd8 downregulation.","authors":"Shuzo Matsubara, Kanae Matsuda-Ito, Haruka Sekiryu, Hiroyoshi Doi, Takumi Nakagawa, Naoya Murao, Hisanobu Oda, Kinichi Nakashima, Taito Matsuda","doi":"10.1038/s44318-025-00455-8","DOIUrl":"10.1038/s44318-025-00455-8","url":null,"abstract":"Neural stem cells (NSCs) in the mammalian brain decline rapidly with age, leading to impairment of hippocampal memory function in later life. However, the relationship between epigenetic remodeling and transcriptional regulation that compromises hippocampal NSC activity during the early stage of chronological aging remains unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) on NSCs and newly generated neurons across different stages. Integrated data analysis revealed continuous alterations in the chromatin profile of hippocampal NSCs and their progeny from neonatal to mature adult stages, accompanied by consistent changes in transcriptional profiles. Further, decreased expression of Setd8, encoding the enzyme for histone H4 monomethylation at lysine 20 (H4K20me1), underlies age-related changes in mouse hippocampal NSCs. Notably, depletion of Setd8 elicits alterations in gene expression and epigenetic regulation that phenocopy age-related changes, and impairs NSC activity, leading to hippocampal memory deficits. Together, our study provides a global map of longitudinal chromatin and transcriptome changes during brain aging and identifies mechanistic insights into early-onset decline of NSC activity and hippocampal neurogenesis that precedes functional aging.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"3645-3668"},"PeriodicalIF":9.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12218407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217446","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

MPS1 promotes timely spindle bipolarization to prevent kinetochore-microtubule attachment errors in oocytes. MPS1及时促进纺锤体双极化，以防止卵母细胞中着丝点-微管附着错误。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-07-01 Epub Date: 2025-06-04 DOI: 10.1038/s44318-025-00461-w

Shuhei Yoshida, Reiko Nakagawa, Kohei Asai, Tomoya S Kitajima

引用次数: 0