EMBO Journal最新文献_第10页

Structural insight into Okazaki fragment maturation mediated by PCNA-bound FEN1 and RNaseH2. 从结构上洞察由 PCNA 结合的 FEN1 和 RNaseH2 介导的冈崎片段成熟。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1038/s44318-024-00296-x

Yuhui Tian, Ningning Li, Qing Li, Ning Gao

{"title":"Structural insight into Okazaki fragment maturation mediated by PCNA-bound FEN1 and RNaseH2.","authors":"Yuhui Tian, Ningning Li, Qing Li, Ning Gao","doi":"10.1038/s44318-024-00296-x","DOIUrl":"10.1038/s44318-024-00296-x","url":null,"abstract":"PCNA is a master coordinator of many DNA-metabolic events. During DNA replication, the maturation of Okazaki fragments involves at least four DNA enzymes, all of which contain PCNA-interacting motifs. However, the temporal relationships and functional modulations between these PCNA-binding proteins are unclear. Here, we developed a strategy to purify endogenous PCNA-containing complexes from native chromatin, and characterized their structures using cryo-EM. Two structurally resolved classes (PCNA-FEN1 and PCNA-FEN1-RNaseH2 complexes) have captured a series of 3D snapshots for the primer-removal steps of Okazaki fragment maturation. These structures show that product release from FEN1 is a rate-liming step. Furthermore, both FEN1 and RNaseH2 undergo continuous conformational changes on PCNA that result in constant fluctuations in the bending angle of substrate DNA at the nick site, implying that these enzymes could regulate each other through conformational modulation of the bound DNA. The structures of the PCNA-FEN1-RNaseH2 complex confirm the toolbelt function of PCNA and suggests a potential unrecognized role of RNaseH2, as a dsDNA binding protein, in promoting the 5'-flap cleaving activity of FEN1.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"484-504"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693737","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

Histone methyltransferases MLL2 and SETD1A/B play distinct roles in H3K4me3 deposition during the transition from totipotency to pluripotency. 组蛋白甲基转移酶MLL2和SETD1A/B在H3K4me3从全能性向多能性转变的过程中发挥着不同的作用。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-12-05 DOI: 10.1038/s44318-024-00329-5

Jingjing Zhang, Qiaoran Sun, Liang Liu, Shichun Yang, Xia Zhang, Yi-Liang Miao, Xin Liu

{"title":"Histone methyltransferases MLL2 and SETD1A/B play distinct roles in H3K4me3 deposition during the transition from totipotency to pluripotency.","authors":"Jingjing Zhang, Qiaoran Sun, Liang Liu, Shichun Yang, Xia Zhang, Yi-Liang Miao, Xin Liu","doi":"10.1038/s44318-024-00329-5","DOIUrl":"10.1038/s44318-024-00329-5","url":null,"abstract":"In early mammalian embryogenesis, a shift from non-canonical histone H3 lysine 4 trimethylation (H3K4me3) linked to transcriptional repression to canonical H3K4me3 indicating active promoters occurs during zygotic genome activation (ZGA). However, the mechanisms and roles of these H3K4me3 states in embryogenesis remain poorly understood. Our research reveals that the histone methyltransferase MLL2 is responsible for installing H3K4me3 (both non-canonical and canonical) in totipotent embryos, while a transition to SETD1A/B-deposited H3K4me3 occurs in pluripotent embryos. Interestingly, MLL2-mediated H3K4me3 operates independently of transcription, fostering a relaxed chromatin state conducive to totipotency rather than directly influencing transcription. Conversely, SETD1A/B-mediated H3K4me3, which depends on transcription, is crucial for facilitating expression of genes essential for pluripotency and pre-implantation development. Our findings highlight the role of the H3K4me3 transition, mediated by an MLL2-to-SETD1A/B relay mechanism, in the regulation of transition from totipotency to pluripotency during early embryogenesis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"437-456"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787650","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

Layered entrenchment maintains essentiality in the evolution of Form I Rubisco complexes. 在形式 I Rubisco 复合物的进化过程中，层状堑壕保持了基本性。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-11-18 DOI: 10.1038/s44318-024-00311-1

Luca Schulz, Jan Zarzycki, Wieland Steinchen, Georg K A Hochberg, Tobias J Erb

{"title":"Layered entrenchment maintains essentiality in the evolution of Form I Rubisco complexes.","authors":"Luca Schulz, Jan Zarzycki, Wieland Steinchen, Georg K A Hochberg, Tobias J Erb","doi":"10.1038/s44318-024-00311-1","DOIUrl":"10.1038/s44318-024-00311-1","url":null,"abstract":"Protein complexes composed of strictly essential subunits are abundant in nature and often arise through the gradual complexification of ancestral precursor proteins. Essentiality can arise through the accumulation of changes that are tolerated in the complex state but would be deleterious for the standalone complex components. While this theoretical framework to explain how essentiality arises has been proposed long ago, it is unclear which factors cause essentiality to persist over evolutionary timescales. In this work we show that the central enzyme of photosynthesis, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), can easily start to depend on a newly recruited interaction partner through multiple, genetically distinct mechanisms that affect stability, solubility, and catalysis. We demonstrate that layering multiple mechanisms of essentiality can lead to its persistence, even if any given mechanism reverts. More broadly, our work highlights that new interaction partners can drastically re-shape which substitutions are tolerated in the proteins they are recruited into. This can lead to the evolution of multilayered essentiality through the exploration of areas of sequence space that are only accessible in the complex state.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"269-280"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669701","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

Intestinal NUCB2/nesfatin-1 regulates hepatic glucose production via the MC4R-cAMP-GLP-1 pathway. 肠道 NUCB2/nesfatin-1 通过 MC4R-cAMP-GLP-1 途径调节肝脏葡萄糖的产生。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-11-19 DOI: 10.1038/s44318-024-00300-4

Shan Geng, Shan Yang, Xuejiao Tang, Shiyao Xue, Ke Li, Dongfang Liu, Chen Chen, Zhiming Zhu, Hongting Zheng, Yuanqiang Wang, Gangyi Yang, Ling Li, Mengliu Yang

{"title":"Intestinal NUCB2/nesfatin-1 regulates hepatic glucose production via the MC4R-cAMP-GLP-1 pathway.","authors":"Shan Geng, Shan Yang, Xuejiao Tang, Shiyao Xue, Ke Li, Dongfang Liu, Chen Chen, Zhiming Zhu, Hongting Zheng, Yuanqiang Wang, Gangyi Yang, Ling Li, Mengliu Yang","doi":"10.1038/s44318-024-00300-4","DOIUrl":"10.1038/s44318-024-00300-4","url":null,"abstract":"Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut - brain - liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"54-74"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677405","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

De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder. LRRC8C的新生变异导致本构通道激活，导致人类多系统疾病。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-12-02 DOI: 10.1038/s44318-024-00322-y

Mathieu Quinodoz, Sonja Rutz, Virginie Peter, Livia Garavelli, A Micheil Innes, Elena F Lehmann, Stephan Kellenberger, Zhong Peng, Angelica Barone, Belinda Campos-Xavier, Sheila Unger, Carlo Rivolta, Raimund Dutzler, Andrea Superti-Furga

{"title":"De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder.","authors":"Mathieu Quinodoz, Sonja Rutz, Virginie Peter, Livia Garavelli, A Micheil Innes, Elena F Lehmann, Stephan Kellenberger, Zhong Peng, Angelica Barone, Belinda Campos-Xavier, Sheila Unger, Carlo Rivolta, Raimund Dutzler, Andrea Superti-Furga","doi":"10.1038/s44318-024-00322-y","DOIUrl":"10.1038/s44318-024-00322-y","url":null,"abstract":"Volume-regulated anion channels (VRACs) are multimeric proteins composed of different paralogs of the LRRC8 family. They are activated in response to hypotonic swelling, but little is known about their specific functions. We studied two human individuals with the same congenital syndrome affecting blood vessels, brain, eyes, and bones. The LRRC8C gene harbored de novo variants in both patients, located in a region of the gene encoding the boundary between the pore and a cytoplasmic domain, which is depleted of sequence variations in control subjects. When studied by cryo-EM, both LRRC8C mutant proteins assembled as their wild-type counterparts, but showed increased flexibility, suggesting a destabilization of subunit interactions. When co-expressed with the obligatory LRRC8A subunit, the mutants exhibited enhanced activation, resulting in channel activity even at isotonic conditions in which wild-type channels are closed. We conclude that structural perturbations of LRRC8C impair channel gating and constitute the mechanistic basis of the dominant gain-of-function effect of these pathogenic variants. The pleiotropic phenotype of this novel clinical entity associated with monoallelic LRRC8C variants indicates the fundamental roles of VRACs in different tissues and organs.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"413-436"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774560","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

Structure of the Nipah virus polymerase complex. 尼帕病毒聚合酶复合物的结构。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-12-30 DOI: 10.1038/s44318-024-00321-z

Esra Balıkçı, Franziska Günl, Loïc Carrique, Jeremy R Keown, Ervin Fodor, Jonathan M Grimes

{"title":"Structure of the Nipah virus polymerase complex.","authors":"Esra Balıkçı, Franziska Günl, Loïc Carrique, Jeremy R Keown, Ervin Fodor, Jonathan M Grimes","doi":"10.1038/s44318-024-00321-z","DOIUrl":"10.1038/s44318-024-00321-z","url":null,"abstract":"Nipah virus is a highly virulent zoonotic paramyxovirus causing severe respiratory and neurological disease. Despite its lethality, there is no approved treatment for Nipah virus infection. The viral polymerase complex, composed of the polymerase (L) and phosphoprotein (P), replicates and transcribes the viral RNA genome. Here, we describe structures of the Nipah virus L-P polymerase complex and the L-protein's Connecting Domain (CD). The cryo-electron microscopy L-P complex structure reveals the organization of the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L-protein, and shows how the P-protein, which forms a tetramer, interacts with the RdRp-domain of the L-protein. The crystal structure of the CD-domain alone reveals binding of three Mg ions. Modelling of this domain onto an AlphaFold 3 model of an RNA-L-P complex suggests a catalytic role for one Mg ion in mRNA capping. These findings offer insights into the structural details of the L-P polymerase complex and the molecular interactions between L-protein and P-protein, shedding light on the mechanisms of the replication machinery. This work will underpin efforts to develop antiviral drugs that target the polymerase complex of Nipah virus.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"563-586"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910752","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 transcription factor Dof3.6/OBP3 regulates iron homeostasis in Arabidopsis. 转录因子Dof3.6/OBP3调节拟南芥的铁稳态。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-11-13 DOI: 10.1038/s44318-024-00304-0

Peipei Xu, Yilin Yang, Zhongtian Zhao, Jinbo Hu, Junyan Xie, Lihua Wang, Huiqiong Zheng, Weiming Cai

{"title":"The transcription factor Dof3.6/OBP3 regulates iron homeostasis in Arabidopsis.","authors":"Peipei Xu, Yilin Yang, Zhongtian Zhao, Jinbo Hu, Junyan Xie, Lihua Wang, Huiqiong Zheng, Weiming Cai","doi":"10.1038/s44318-024-00304-0","DOIUrl":"10.1038/s44318-024-00304-0","url":null,"abstract":"Iron is an essential element for plants. Iron uptake by plants is highly regulated, but the underlying mechanism is poorly understood. Using a truncated fragment of the iron deficiency-responsive bHLH100 gene promoter, we screened the Arabidopsis transcription factor yeast one-hybrid (Y1H) library and identified the DOF family protein, OBP3, as a crucial component of the iron deficiency-signaling pathway. OBP3 is a transcriptional repressor with a C-terminal activation domain. Its expression is induced by iron deficiency. The transgenic lines that overexpress OBP3 exhibited iron overload and premature leaf necrosis, while the obp3 mutant was less tolerant of iron deficiency. It was discovered that OBP3 directly targets the Ib subgroup of bHLH gene promoters. OBP3 interacts with the bHLH transcription factor ILR3 (IAA-LEUCINE RESISTANT3), and their interaction enhances the DNA-binding ability and transcriptional promoting activity of OBP3, resulting in the positive regulation of iron deficiency-response genes. In addition, the E3 Ligase BRUTUS facilitates 26S proteasome-mediated degradation of OBP3 protein to prevent excessive iron uptake in plants. In conclusion, our research emphasizes the vital role of OBP3 in regulating plant iron homeostasis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"251-268"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631882","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

STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NF-κB signaling. STING 可诱导 HOIP 介导的 M1 泛素链合成，从而刺激 NF-κB 信号传导。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1038/s44318-024-00291-2

Tara D Fischer, Eric N Bunker, Peng-Peng Zhu, François Le Guerroué, Mahan Hadjian, Eunice Dominguez-Martin, Francesco Scavone, Robert Cohen, Tingting Yao, Yan Wang, Achim Werner, Richard J Youle

{"title":"STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NF-κB signaling.","authors":"Tara D Fischer, Eric N Bunker, Peng-Peng Zhu, François Le Guerroué, Mahan Hadjian, Eunice Dominguez-Martin, Francesco Scavone, Robert Cohen, Tingting Yao, Yan Wang, Achim Werner, Richard J Youle","doi":"10.1038/s44318-024-00291-2","DOIUrl":"10.1038/s44318-024-00291-2","url":null,"abstract":"STING activation by cyclic dinucleotides induces IRF3- and NF-κB-mediated gene expression in mammals, as well as lipidation of LC3B at Golgi-related membranes. While mechanisms of the IRF3 response are well understood, the mechanisms of NF-κB activation via STING remain unclear. We report here that STING activation induces linear/M1-linked ubiquitin chain (M1-Ub) formation and recruitment of the LUBAC E3 ligase, HOIP, to LC3B-associated Golgi membranes where ubiquitin is also localized. Loss of HOIP prevents formation of M1-Ub chains and reduces STING-induced NF-κB and IRF3 signaling in human THP1 monocytes and mouse bone marrow-derived macrophages, without affecting STING activation. STING-induced LC3B lipidation is not required for M1-Ub chain formation or for immune-related gene expression, but the recently reported STING function in neutralizing Golgi pH may be involved. Thus, LUBAC synthesis of M1-linked ubiquitin chains mediates STING-induced innate immune signaling.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"141-165"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693734","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

FNDC1 is a myokine that promotes myogenesis and muscle regeneration. FNDC1 是一种肌动蛋白，可促进肌肉生成和肌肉再生。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-11-20 DOI: 10.1038/s44318-024-00285-0

Rui Xin Zhang, Yuan Yuan Zhai, Rong Rong Ding, Jia He Huang, Xiao Chen Shi, Huan Liu, Xiao Peng Liu, Jian Feng Zhang, Jun Feng Lu, Zhe Zhang, Xiang Kai Leng, De Fu Li, Jun Ying Xiao, Bo Xia, Jiang Wei Wu

{"title":"FNDC1 is a myokine that promotes myogenesis and muscle regeneration.","authors":"Rui Xin Zhang, Yuan Yuan Zhai, Rong Rong Ding, Jia He Huang, Xiao Chen Shi, Huan Liu, Xiao Peng Liu, Jian Feng Zhang, Jun Feng Lu, Zhe Zhang, Xiang Kai Leng, De Fu Li, Jun Ying Xiao, Bo Xia, Jiang Wei Wu","doi":"10.1038/s44318-024-00285-0","DOIUrl":"10.1038/s44318-024-00285-0","url":null,"abstract":"Myogenesis is essential for skeletal muscle formation and regeneration after injury, yet its regulators are largely unknown. Here we identified fibronectin type III domain containing 1 (FNDC1) as a previously uncharacterized myokine. In vitro studies showed that knockdown of Fndc1 in myoblasts reduces myotube formation, while overexpression of Fndc1 promotes myogenic differentiation. We further generated recombinant truncated mouse FNDC1 (mFNDC1), which retains reliable activity in promoting myoblast differentiation in vitro. Gain- and loss-of-function studies collectively showed that FNDC1 promotes cardiotoxin (CTX)-induced muscle regeneration in adult mice. Furthermore, recombinant FNDC1 treatment ameliorated pathological muscle phenotypes in the mdx mouse model of Duchenne muscular dystrophy. Mechanistically, FNDC1 bound to the integrin α5β1 and activated the downstream FAK/PI3K/AKT/mTOR pathway to promote myogenic differentiation. Pharmacological inhibition of integrin α5β1 or of the downstream FAK/PI3K/AKT/mTOR pathway abolished the pro-myogenic effect of FNDC1. Collectively, these results suggested that myokine FNDC1 might be used as a therapeutic agent to regulate myogenic differentiation and muscle regeneration for the treatment of acute and chronic muscle disease.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"30-53"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683430","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

Meiotic DNA break resection and recombination rely on chromatin remodeler Fun30. 减数分裂DNA断裂切除和重组依赖于染色质重塑器Fun30。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-11-29 DOI: 10.1038/s44318-024-00318-8

Pei-Ching Huang, Soogil Hong, Hasan F Alnaser, Eleni P Mimitou, Keun P Kim, Hajime Murakami, Scott Keeney

{"title":"Meiotic DNA break resection and recombination rely on chromatin remodeler Fun30.","authors":"Pei-Ching Huang, Soogil Hong, Hasan F Alnaser, Eleni P Mimitou, Keun P Kim, Hajime Murakami, Scott Keeney","doi":"10.1038/s44318-024-00318-8","DOIUrl":"10.1038/s44318-024-00318-8","url":null,"abstract":"DNA double-strand breaks (DSBs) are nucleolytically processed to generate single-stranded DNA for homologous recombination. In Saccharomyces cerevisiae meiosis, this resection involves nicking by the Mre11-Rad50-Xrs2 complex (MRX), then exonucleolytic digestion by Exo1. Chromatin remodeling at meiotic DSBs is thought necessary for resection, but the remodeling enzyme was unknown. Here we show that the SWI/SNF-like ATPase Fun30 plays a major, nonredundant role in meiotic resection. A fun30 mutation shortened resection tracts almost as severely as an exo1-nd (nuclease-dead) mutation, and resection was further shortened in a fun30 exo1-nd double mutant. Fun30 associates with chromatin in response to DSBs, and the constitutive positioning of nucleosomes governs resection endpoint locations in the absence of Fun30. We infer that Fun30 promotes both the MRX- and Exo1-dependent steps in resection, possibly by removing nucleosomes from broken chromatids. Moreover, the extremely short resection in fun30 exo1-nd double mutants is accompanied by compromised interhomolog recombination bias, leading to defects in recombination and chromosome segregation. Thus, this study also provides insight about the minimal resection lengths needed for robust recombination.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"200-224"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755885","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