EMBO Journal最新文献_第3页

NANOG is repurposed after implantation to repress Sox2 and begin pluripotency extinction. NANOG在植入后被重新利用以抑制Sox2并开始多能性消失。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-10-01 Epub Date: 2025-08-18 DOI: 10.1038/s44318-025-00527-9

Frederick C K Wong, Man Zhang, Ella Thomson, Linus J Schumacher, Anestis Tsakiridis, James Ashmore, Tong Li, Guillaume Blin, Eleni Karagianni, Nicholas P Mullin, Ian Chambers, Valerie Wilson

{"title":"NANOG is repurposed after implantation to repress Sox2 and begin pluripotency extinction.","authors":"Frederick C K Wong, Man Zhang, Ella Thomson, Linus J Schumacher, Anestis Tsakiridis, James Ashmore, Tong Li, Guillaume Blin, Eleni Karagianni, Nicholas P Mullin, Ian Chambers, Valerie Wilson","doi":"10.1038/s44318-025-00527-9","DOIUrl":"10.1038/s44318-025-00527-9","url":null,"abstract":"Loss of pluripotency is an essential step in post-implantation development that facilitates the emergence of somatic cell identities essential for gastrulation. Before implantation, pluripotent cell identity is governed by a gene regulatory network that includes the key transcription factors SOX2 and NANOG. However, it is unclear how the pluripotency gene regulatory network is dissolved to enable lineage restriction. Here, we show that SOX2 is required for post-implantation pluripotent identity in the mouse, and cells that lose SOX2 expression in the posterior epiblast are no longer pluripotent. Using in vitro and in vivo analyses, we demonstrate anticorrelated expression of NANOG and SOX2 preceding gastrulation, culminating in an early disappearance of pluripotent identity from posterior NANOGhigh/SOX2low epiblast. Surprisingly, Sox2 expression is repressed by NANOG and embryos with post-implantation deletion of Nanog maintain posterior SOX2 expression. Our results demonstrate that the distinctive features of post-implantation pluripotency are underpinned by altered functionality of pluripotency transcription factors, ensuring correct spatio-temporal loss of embryonic pluripotency.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5337-5374"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876543","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

RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis. RTN4IP1在线粒体复合体I组装和CoQ生物合成的最后阶段是必需的。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-10-01 Epub Date: 2025-08-26 DOI: 10.1038/s44318-025-00533-x

Monika Oláhová, Rachel M Guerra, Jack J Collier, Juliana Heidler, Kyle Thompson, Chelsea R White, Paulina Castañeda-Tamez, Alfredo Cabrera-Orefice, Robert N Lightowlers, Zofia M A Chrzanowska-Lightowlers, Alexander Galkin, Ilka Wittig, David J Pagliarini, Robert W Taylor

{"title":"RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis.","authors":"Monika Oláhová, Rachel M Guerra, Jack J Collier, Juliana Heidler, Kyle Thompson, Chelsea R White, Paulina Castañeda-Tamez, Alfredo Cabrera-Orefice, Robert N Lightowlers, Zofia M A Chrzanowska-Lightowlers, Alexander Galkin, Ilka Wittig, David J Pagliarini, Robert W Taylor","doi":"10.1038/s44318-025-00533-x","DOIUrl":"10.1038/s44318-025-00533-x","url":null,"abstract":"A biochemical deficiency of mitochondrial complex I (CI) underlies approximately 30% of cases of primary mitochondrial disease, yet the inventory of molecular machinery required for CI assembly remains incomplete. We previously characterised patients with isolated CI deficiency caused by segregating variants in RTN4IP1, a gene that encodes a mitochondrial NAD(P)H oxidoreductase. Here, we demonstrate that RTN4IP1 deficiency causes a CI assembly defect in both patient fibroblasts and knockout cells, and report that RTN4IP1 is a bona fide CI assembly factor. Complexome profiling revealed accumulation of unincorporated ND5-module and impaired N-module production. RTN4IP1 patient fibroblasts also exhibited defective coenzyme Q biosynthesis, substantiating a second function of RTN4IP1. Thus, our data reveal RTN4IP1 plays necessary and independent roles in both the terminal stages of CI assembly and in coenzyme Q metabolism, and that pathogenic RTN4IP1 variants impair both functions in patients with mitochondrial disease.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5482-5508"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977305","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

Embryonic signatures of intergenerational epigenetic inheritance across paternal environments and genetic backgrounds. 跨父系环境和遗传背景的代际表观遗传的胚胎特征。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-09-26 DOI: 10.1038/s44318-025-00556-4

Mathilde Dura, Bobby Ranjan, Joana B Serrano, Rossella Paribeni, Violetta Paribeni, Laura Villacorta, Vladimir Benes, Olga Boruc, Ana Boskovic, Jamie A Hackett

{"title":"Embryonic signatures of intergenerational epigenetic inheritance across paternal environments and genetic backgrounds.","authors":"Mathilde Dura, Bobby Ranjan, Joana B Serrano, Rossella Paribeni, Violetta Paribeni, Laura Villacorta, Vladimir Benes, Olga Boruc, Ana Boskovic, Jamie A Hackett","doi":"10.1038/s44318-025-00556-4","DOIUrl":"https://doi.org/10.1038/s44318-025-00556-4","url":null,"abstract":"The paternal preconception environment has been implicated as a modulator of phenotypic traits and disease risk in F1 offspring. However, the prevalence and mechanisms of such intergenerational epigenetic inheritance (IEI) in mammals remain poorly defined. Moreover, the interplay between paternal exposure, genetics, and age on emergent offspring features is unexplored. Here, we measure the quantitative impact of three paternal environments on early embryogenesis across genetic backgrounds. Using in vitro fertilisation (IVF) at scale, we capture batch-robust transcriptomic signatures of IEI with single-blastocyst resolution. Amongst these, paternal gut microbiota dysbiosis is linked with aberrant expression of (extra-)embryonic lineage regulators in blastocysts. In contrast, a paternal low-protein high-sugar diet associates with subtle preimplantation growth effects. We further identify gene expression variability as a paternally induced F1 phenotype, and highlight confounding issues for IEI, such as batch effects and under-sampling. Finally, while genetic background dominantly modifies the inherited signature of paternal environment, aged fathers universally impact F1 expression programmes across genetic contexts. This study systematically characterises how paternal conditioning programs subtle but detectable molecular responses in early embryos, and proposes guiding principles to dissect intergenerational phenomenology.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180138","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

BLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM. BLTP3A与晚期内吞途径的膜相关，是CASM的效应物。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-09-11 DOI: 10.1038/s44318-025-00543-9

Michael G Hanna, Hely O Rodriguez Cruz, Kenshiro Fujise, Yumei Wu, C Shan Xu, Song Pang, Zhuonging Li, Mara Monetti, Pietro De Camilli

引用次数: 0

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 : 2025-09-01 Epub 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":"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":"5086-5111"},"PeriodicalIF":8.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436607/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A chimeric Mla-Pqi lipid transport system is required for Brucella abortus survival in macrophages. 嵌合Mla-Pqi脂质转运系统是流产布鲁氏菌在巨噬细胞中存活所必需的。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-09-01 Epub Date: 2025-08-13 DOI: 10.1038/s44318-025-00511-3

Adélie Lannoy, Alexi Ronneau, Miguel Fernández-García, Marc Dieu, Patricia Renard, Antonia García Fernández, Raquel Condez-Alvarez, Xavier De Bolle

{"title":"A chimeric Mla-Pqi lipid transport system is required for Brucella abortus survival in macrophages.","authors":"Adélie Lannoy, Alexi Ronneau, Miguel Fernández-García, Marc Dieu, Patricia Renard, Antonia García Fernández, Raquel Condez-Alvarez, Xavier De Bolle","doi":"10.1038/s44318-025-00511-3","DOIUrl":"10.1038/s44318-025-00511-3","url":null,"abstract":"The cell envelope of gram-negative bacteria is composed of an inner and an outer membrane. In Escherichia coli, several pathways mediate phospholipid transport between the two membranes, including the Mla (i.e., maintenance of lipid asymmetry) and Pqi (i.e., paraquat inducible) systems. Here, we identify and characterise in the intracellular pathogen Brucella abortus a complex named Mpc, which exhibits homology to both Mla and Pqi components. Mpc is required for bacterial growth under envelope stress conditions, and for survival within macrophages during the early stages of infection. Analyses of protein-protein interactions and structural predictions suggest that the Mpc complex bridges the two membranes of the bacterial cell envelope. Absence of this system results in altered lipid composition of the outer membrane vesicles, indicating that Mpc plays a role in lipid transport between the membranes. Our sequence comparisons reveal that Mpc is conserved across numerous species of Hyphomicrobiales. The discovery of this novel lipid-trafficking system expands our understanding of the diversity and evolution of lipid-transport mechanisms in diderm bacteria.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5066-5085"},"PeriodicalIF":8.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849500","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

Eliminating separase inhibition reveals absence of robust cohesin protection in oocyte metaphase II. 消除分离酶抑制表明卵母细胞中期缺乏强大的黏结蛋白保护。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-09-01 Epub Date: 2025-08-05 DOI: 10.1038/s44318-025-00522-0

Safia El Jailani, Damien Cladière, Elvira Nikalayevich, Sandra A Touati, Vera Chesnokova, Shlomo Melmed, Eulalie Buffin, Katja Wassmann

{"title":"Eliminating separase inhibition reveals absence of robust cohesin protection in oocyte metaphase II.","authors":"Safia El Jailani, Damien Cladière, Elvira Nikalayevich, Sandra A Touati, Vera Chesnokova, Shlomo Melmed, Eulalie Buffin, Katja Wassmann","doi":"10.1038/s44318-025-00522-0","DOIUrl":"10.1038/s44318-025-00522-0","url":null,"abstract":"The meiotic segregation pattern to generate haploid gametes is mediated by step-wise cohesion removal by separase, first from chromosome arms in meiosis I, and then from the pericentromere in meiosis II. In mammalian oocytes, separase is tightly controlled during the hours-long prometaphase and until chromosome segregation in meiosis I, activated for a short time window, and again inhibited until metaphase II arrest is lifted by fertilization. Centromeric cohesin is protected from cleavage by Sgo2-PP2A in meiosis I. It remained enigmatic how tight control of alternating separase activation and inactivation is achieved during the two divisions in oocytes, and when cohesin protection is put in place and removed. Using complementation assays in knock-out mouse models, we established the contributions of cyclin B1 and securin for separase inhibition during both divisions. When eliminating separase inhibition, we found that cohesin is not robustly protected at meiosis I resumption and during metaphase II arrest. Importantly, in meiosis II, the sole event required for cleavage of pericentromeric cohesin besides separase activation is prior kinetochore individualization in meiosis I.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5187-5214"},"PeriodicalIF":8.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790562","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

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis. 靶向SUMO2逆转由SS18::SSX融合癌蛋白驱动的异常表观遗传重布线，并损害肉瘤发生。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-09-01 Epub Date: 2025-08-13 DOI: 10.1038/s44318-025-00526-w

Rema Iyer, Anagha Deshpande, Aditi Pedgaonkar, Pramod Akula Bala, Taehee Kim, Gerard L Brien, Darren Finlay, Kristiina Vuori, Alice Soragni, Hiromi I Wetterstein, Rabi Murad, Aniruddha J Deshpande

{"title":"Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis.","authors":"Rema Iyer, Anagha Deshpande, Aditi Pedgaonkar, Pramod Akula Bala, Taehee Kim, Gerard L Brien, Darren Finlay, Kristiina Vuori, Alice Soragni, Hiromi I Wetterstein, Rabi Murad, Aniruddha J Deshpande","doi":"10.1038/s44318-025-00526-w","DOIUrl":"10.1038/s44318-025-00526-w","url":null,"abstract":"Synovial sarcoma (SySa) is an aggressive soft tissue sarcoma with an urgent need to develop targeted therapies. Here, we exploited specific vulnerabilities created by transcriptional rewiring by the fusion protein SS18::SSX, the sole oncogenic driver in SySa. To uncover genes that are selectively essential for the fitness of SySa cells compared to other tumor cell lines, we mined the Cancer-Dependency-Map data. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) constituted one of the strongest dependencies both in vitro and in vivo. TAK-981, a clinical-stage small-molecule SUMO2 inhibitor potently suppressed growth and colony-forming ability. Transcriptomic profiling showed that SUMO2 inhibition elicited a profound reversal of the gene expression program orchestrated by SS18::SSX fusion. Further, genetic depletion or SUMO2 inhibition reduced global expression levels and chromatin occupancy of the SS18::SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark facilitating SySa pathogenesis. Taken together, our study identifies SUMO2 as a novel, selective vulnerability in synovial sarcoma, suggesting new avenues for targeted treatment of soft tissue tumors.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4984-5004"},"PeriodicalIF":8.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849501","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

cGAS-STING are responsible for premature aging of telomerase-deficient zebrafish. cGAS-STING与端粒酶缺陷斑马鱼的早衰有关。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-09-01 Epub Date: 2025-06-09 DOI: 10.1038/s44318-025-00482-5

Naz Şerifoğlu, Giulia Allavena, Bruno Lopes-Bastos, Marta Marzullo, Andreia Marques, Pauline Colibert, Pavlos Bousounis, Eirini Trompouki, Miguel Godinho Ferreira

{"title":"cGAS-STING are responsible for premature aging of telomerase-deficient zebrafish.","authors":"Naz Şerifoğlu, Giulia Allavena, Bruno Lopes-Bastos, Marta Marzullo, Andreia Marques, Pauline Colibert, Pavlos Bousounis, Eirini Trompouki, Miguel Godinho Ferreira","doi":"10.1038/s44318-025-00482-5","DOIUrl":"10.1038/s44318-025-00482-5","url":null,"abstract":"Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA-damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type-I interferon-based inflammation and senescence. However, the consequences of these events for the organism are not yet understood. Here, we show that sting is responsible for premature aging of telomerase-deficient zebrafish. We generated sting-/- tert-/- double-mutant animals and observed a thorough rescue of tert-/- phenotypes. At the cellular level, lack of cGAS-STING in tert mutants resulted in reduced senescence, increased cell proliferation, and decreased inflammation despite similarly short telomeres. Critically, absence of sting function resulted in dampening of the DNA damage response and reduced p53 levels. At the organism level, sting-/- tert-/- zebrafish regained fertility, showed delayed cachexia, and decreased cancer incidence, resulting in increased healthspan and lifespan of telomerase mutant animals.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4666-4680"},"PeriodicalIF":8.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259267","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

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 8.3 1区生物学

EMBO Journal Pub Date : 2025-09-01 Epub 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":"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":"4899-4917"},"PeriodicalIF":8.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402098/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0