EMBO Reports最新文献_第6页

Recognition of phylogenetically diverse pathogens through enzymatically amplified recruitment of RNF213. 通过 RNF213 的酶扩增招募识别系统发育不同的病原体。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-01 Epub Date: 2024-10-07 DOI: 10.1038/s44319-024-00280-w

Ana Crespillo-Casado, Prathyush Pothukuchi, Katerina Naydenova, Matthew C J Yip, Janet M Young, Jerome Boulanger, Vimisha Dharamdasani, Ceara Harper, Pierre-Mehdi Hammoudi, Elsje G Otten, Keith Boyle, Mayuri Gogoi, Harmit S Malik, Felix Randow

{"title":"Recognition of phylogenetically diverse pathogens through enzymatically amplified recruitment of RNF213.","authors":"Ana Crespillo-Casado, Prathyush Pothukuchi, Katerina Naydenova, Matthew C J Yip, Janet M Young, Jerome Boulanger, Vimisha Dharamdasani, Ceara Harper, Pierre-Mehdi Hammoudi, Elsje G Otten, Keith Boyle, Mayuri Gogoi, Harmit S Malik, Felix Randow","doi":"10.1038/s44319-024-00280-w","DOIUrl":"10.1038/s44319-024-00280-w","url":null,"abstract":"Innate immunity senses microbial ligands known as pathogen-associated molecular patterns (PAMPs). Except for nucleic acids, PAMPs are exceedingly taxa-specific, thus enabling pattern recognition receptors to detect cognate pathogens while ignoring others. How the E3 ubiquitin ligase RNF213 can respond to phylogenetically distant pathogens, including Gram-negative Salmonella, Gram-positive Listeria, and eukaryotic Toxoplasma, remains unknown. Here we report that the evolutionary history of RNF213 is indicative of repeated adaptation to diverse pathogen target structures, especially in and around its newly identified CBM20 carbohydrate-binding domain, which we have resolved by cryo-EM. We find that RNF213 forms coats on phylogenetically distant pathogens. ATP hydrolysis by RNF213's dynein-like domain is essential for coat formation on all three pathogens studied as is RZ finger-mediated E3 ligase activity for bacteria. Coat formation is not diffusion-limited but instead relies on rate-limiting initiation events and subsequent cooperative incorporation of further RNF213 molecules. We conclude that RNF213 responds to evolutionarily distant pathogens through enzymatically amplified cooperative recruitment.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4979-5005"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388946","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

Structural insights into human zinc transporter ZnT1 mediated Zn²⁺ efflux. 人类锌转运体 ZnT1 介导的 Zn2+ 外流的结构研究。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-01 Epub Date: 2024-10-10 DOI: 10.1038/s44319-024-00287-3

Yonghui Long, Zhini Zhu, Zixuan Zhou, Chuanhui Yang, Yulin Chao, Yuwei Wang, Qingtong Zhou, Ming-Wei Wang, Qianhui Qu

{"title":"Structural insights into human zinc transporter ZnT1 mediated Zn2+ efflux.","authors":"Yonghui Long, Zhini Zhu, Zixuan Zhou, Chuanhui Yang, Yulin Chao, Yuwei Wang, Qingtong Zhou, Ming-Wei Wang, Qianhui Qu","doi":"10.1038/s44319-024-00287-3","DOIUrl":"10.1038/s44319-024-00287-3","url":null,"abstract":"Zinc transporter 1 (ZnT1), the principal carrier of cytosolic zinc to the extracellular milieu, is important for cellular zinc homeostasis and resistance to zinc toxicity. Despite recent advancements in the structural characterization of various zinc transporters, the mechanism by which ZnTs-mediated Zn2+ translocation is coupled with H+ or Ca2+ remains unclear. To visualize the transport dynamics, we determined the cryo-electron microscopy (cryo-EM) structures of human ZnT1 at different functional states. ZnT1 dimerizes via extensive interactions between the cytosolic (CTD), the transmembrane (TMD), and the unique cysteine-rich extracellular (ECD) domains. At pH 7.5, both protomers adopt an outward-facing (OF) conformation, with Zn2+ ions coordinated at the TMD binding site by distinct compositions. At pH 6.0, ZnT1 complexed with Zn2+ exhibits various conformations [OF/OF, OF/IF (inward-facing), and IF/IF]. These conformational snapshots, together with biochemical investigation and molecular dynamic simulations, shed light on the mechanism underlying the proton-dependence of ZnT1 transport.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"5006-5025"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399763","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

AI-driven biology: rethinking experiments and computation : An interview with Michael Bronstein, DeepMind Professor of Artificial Intelligence at the University of Oxford and Founding Scientific Director of the Aithyra Institute of the Austrian Academy of Sciences. 人工智能驱动的生物学：重新思考实验和计算：采访牛津大学 DeepMind 人工智能教授、奥地利科学院艾思拉研究所创始科学主任迈克尔-布朗斯坦。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-01 Epub Date: 2024-09-23 DOI: 10.1038/s44319-024-00268-6

Thomas Lemberger

引用次数: 0

Leishmania protein KMP-11 modulates cholesterol transport and membrane fluidity to facilitate host cell invasion. 利什曼病菌蛋白 KMP-11 可调节胆固醇转运和膜流动性，从而促进宿主细胞入侵。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-31 DOI: 10.1038/s44319-024-00302-7

Achinta Sannigrahi, Souradeepa Ghosh, Supratim Pradhan, Pulak Jana, Junaid Jibran Jawed, Subrata Majumdar, Syamal Roy, Sanat Karmakar, Budhaditya Mukherjee, Krishnananda Chattopadhyay

{"title":"Leishmania protein KMP-11 modulates cholesterol transport and membrane fluidity to facilitate host cell invasion.","authors":"Achinta Sannigrahi, Souradeepa Ghosh, Supratim Pradhan, Pulak Jana, Junaid Jibran Jawed, Subrata Majumdar, Syamal Roy, Sanat Karmakar, Budhaditya Mukherjee, Krishnananda Chattopadhyay","doi":"10.1038/s44319-024-00302-7","DOIUrl":"https://doi.org/10.1038/s44319-024-00302-7","url":null,"abstract":"The first step of successful infection by any intracellular pathogen relies on its ability to invade its host cell membrane. However, the detailed structural and molecular understanding underlying lipid membrane modification during pathogenic invasion remains unclear. In this study, we show that a specific Leishmania donovani (LD) protein, KMP-11, forms oligomers that bridge LD and host macrophage (MΦ) membranes. This KMP-11 induced interaction between LD and MΦ depends on the variations in cholesterol (CHOL) and ergosterol (ERG) contents in their respective membranes. These variations are crucial for the subsequent steps of invasion, including (a) the initial attachment, (b) CHOL transport from MΦ to LD, and (c) detachment of LD from the initial point of contact through a liquid ordered (Lo) to liquid disordered (Ld) membrane-phase transition. To validate the importance of KMP-11, we generate KMP-11 depleted LD, which failed to attach and invade host MΦ. Through tryptophan-scanning mutagenesis and synthesized peptides, we develop a generalized mathematical model, which demonstrates that the hydrophobic moment and the symmetry sequence code at the membrane interacting protein domain are key factors in facilitating the membrane phase transition and, consequently, the host cell infection process by Leishmania parasites.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557440","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 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth. 人类运动后 24 小时的分子状况显示，MYC 足以促进肌肉生长。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-31 DOI: 10.1038/s44319-024-00299-z

Sebastian Edman, Ronald G Jones Iii, Paulo R Jannig, Rodrigo Fernandez-Gonzalo, Jessica Norrbom, Nicholas T Thomas, Sabin Khadgi, Pieter J Koopmans, Francielly Morena, Toby L Chambers, Calvin S Peterson, Logan N Scott, Nicholas P Greene, Vandre C Figueiredo, Christopher S Fry, Liu Zhengye, Johanna T Lanner, Yuan Wen, Björn Alkner, Kevin A Murach, Ferdinand von Walden

{"title":"The 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth.","authors":"Sebastian Edman, Ronald G Jones Iii, Paulo R Jannig, Rodrigo Fernandez-Gonzalo, Jessica Norrbom, Nicholas T Thomas, Sabin Khadgi, Pieter J Koopmans, Francielly Morena, Toby L Chambers, Calvin S Peterson, Logan N Scott, Nicholas P Greene, Vandre C Figueiredo, Christopher S Fry, Liu Zhengye, Johanna T Lanner, Yuan Wen, Björn Alkner, Kevin A Murach, Ferdinand von Walden","doi":"10.1038/s44319-024-00299-z","DOIUrl":"10.1038/s44319-024-00299-z","url":null,"abstract":"A detailed understanding of molecular responses to a hypertrophic stimulus in skeletal muscle leads to therapeutic advances aimed at promoting muscle mass. To decode the molecular factors regulating skeletal muscle mass, we utilized a 24-h time course of human muscle biopsies after a bout of resistance exercise. Our findings indicate: (1) the DNA methylome response at 30 min corresponds to upregulated genes at 3 h, (2) a burst of translation- and transcription-initiation factor-coding transcripts occurs between 3 and 8 h, (3) changes to global protein-coding gene expression peaks at 8 h, (4) ribosome-related genes dominate the mRNA landscape between 8 and 24 h, (5) methylation-regulated MYC is a highly influential transcription factor throughout recovery. To test whether MYC is sufficient for hypertrophy, we periodically pulse MYC in skeletal muscle over 4 weeks. Transient MYC increases muscle mass and fiber size in the soleus of adult mice. We present a temporally resolved resource for understanding molecular adaptations to resistance exercise in muscle ( http://data.myoanalytics.com ) and suggest that controlled MYC doses influence the exercise-related hypertrophic transcriptional landscape.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557442","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

Local translatome sustains synaptic function in impaired Wallerian degeneration. 在沃勒里变性受损的情况下，局部转译体能维持突触功能。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-31 DOI: 10.1038/s44319-024-00301-8

Maria Paglione, Leonardo Restivo, Sarah Zakhia, Arnau Llobet Rosell, Marco Terenzio, Lukas J Neukomm

{"title":"Local translatome sustains synaptic function in impaired Wallerian degeneration.","authors":"Maria Paglione, Leonardo Restivo, Sarah Zakhia, Arnau Llobet Rosell, Marco Terenzio, Lukas J Neukomm","doi":"10.1038/s44319-024-00301-8","DOIUrl":"https://doi.org/10.1038/s44319-024-00301-8","url":null,"abstract":"After injury, severed axons separated from their somas activate programmed axon degeneration, a conserved pathway to initiate their degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after axotomy. How this synaptic function is sustained remains currently unknown. Here, we show that dNmnat overexpression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks. When evoked, they elicit a postsynaptic behavior, a readout for preserved synaptic function. We used ribosomal pulldown to isolate the translatome from these projections 1 week after axotomy. Translatome candidates of enriched biological classes identified by transcriptional profiling are validated in a screen using a novel automated system to detect evoked antennal grooming as a proxy for preserved synaptic function. RNAi-mediated knockdown reveals that transcripts of the mTORC1 pathway, a mediator of protein synthesis, and of candidate genes involved in protein ubiquitination and Ca2+ homeostasis are required for preserved synaptic function. Our translatome dataset also uncovers several uncharacterized Drosophila genes associated with human disease. It may offer insights into novel avenues for therapeutic treatments.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557441","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 Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity. Dectin-1 和 Dectin-2 簇：在免疫中发挥重要作用的 C 型凝集素受体。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-31 DOI: 10.1038/s44319-024-00296-2

Mariano Malamud, Gordon D Brown

{"title":"The Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity.","authors":"Mariano Malamud, Gordon D Brown","doi":"10.1038/s44319-024-00296-2","DOIUrl":"https://doi.org/10.1038/s44319-024-00296-2","url":null,"abstract":"The ability of myeloid cells to recognize and differentiate endogenous or exogenous ligands rely on the presence of different transmembrane protein receptors. C-type lectin receptors (CLRs), defined by the presence of a conserved structural motif called C-type lectin-like domain (CTLD), are a crucial family of receptors involved in this process, being able to recognize a diverse range of ligands from glycans to proteins or lipids and capable of initiating an immune response. The Dectin-1 and Dectin-2 clusters involve two groups of CLRs, with genes genomically linked within the natural killer cluster of genes in both humans and mice, and all characterized by the presence of a single extracellular CTLD. Fundamental immune cell functions such as antimicrobial effector mechanisms as well as internalization and presentation of antigens are induced and/or regulated through activatory, or inhibitory signalling pathways triggered by these receptors after ligand binding. In this review, we will discuss the most recent concepts regarding expression, ligands, signaling pathways and functions of each member of the Dectin clusters of CLRs, highlighting the importance and diversity of their functions.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557443","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

Eicosapentaenoic acid induces macrophage Mox polarization to prevent diabetic cardiomyopathy. 二十碳五烯酸诱导巨噬细胞 Mox 极化以预防糖尿病心肌病。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-31 DOI: 10.1038/s44319-024-00271-x

Jie Li, Wenshan Nan, Xiaoli Huang, Huali Meng, Shue Wang, Yan Zheng, Ying Li, Hui Li, Zhiyue Zhang, Lei Du, Xiao Yin, Hao Wu

{"title":"Eicosapentaenoic acid induces macrophage Mox polarization to prevent diabetic cardiomyopathy.","authors":"Jie Li, Wenshan Nan, Xiaoli Huang, Huali Meng, Shue Wang, Yan Zheng, Ying Li, Hui Li, Zhiyue Zhang, Lei Du, Xiao Yin, Hao Wu","doi":"10.1038/s44319-024-00271-x","DOIUrl":"https://doi.org/10.1038/s44319-024-00271-x","url":null,"abstract":"Diabetic cardiomyopathy (DC) leads to heart failure, with few effective approaches for its intervention. Eicosapentaenoic acid (EPA) is an essential nutrient that benefits the cardiovascular system, but its effect on DC remains unknown. Here, we report that EPA protects against DC in streptozotocin and high-fat diet-induced diabetic mice, with an emphasis on the reduction of cardiac M1-polarized macrophages. In vitro, EPA abrogates cardiomyocyte injury induced by M1-polarized macrophages, switching macrophage phenotype from M1 to Mox, but not M2, polarization. Moreover, macrophage Mox polarization combats M1-polarized macrophage-induced cardiomyocyte injury. Further, heme oxygenase 1 (HO-1) was identified to maintain the Mox phenotype, mediating EPA suppression of macrophage M1 polarization and the consequential cardiomyocyte injury. Mechanistic studies reveal that G-protein-coupled receptor 120 mediates the upregulation of HO-1 by EPA. Notably, EPA promotes Mox polarization in monocyte-derived macrophages from diabetic patients. The current study provides EPA and macrophage Mox polarization as novel strategies for DC intervention.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557439","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

Phosphorylation of P-stalk proteins defines the ribosomal state for interaction with auxiliary protein factors. P-stalk 蛋白的磷酸化决定了核糖体与辅助蛋白因子相互作用的状态。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-28 DOI: 10.1038/s44319-024-00297-1

Kamil Filipek, Sandra Blanchet, Eliza Molestak, Monika Zaciura, Colin Chih-Chien Wu, Patrycja Horbowicz-Drożdżal, Przemysław Grela, Mateusz Zalewski, Sebastian Kmiecik, Alan González-Ibarra, Dawid Krokowski, Przemysław Latoch, Agata L Starosta, Mateusz Mołoń, Yutian Shao, Lidia Borkiewicz, Barbara Michalec-Wawiórka, Leszek Wawiórka, Konrad Kubiński, Katarzyna Socała, Piotr Wlaź, Kyle W Cunningham, Rachel Green, Marina V Rodnina, Marek Tchórzewski

{"title":"Phosphorylation of P-stalk proteins defines the ribosomal state for interaction with auxiliary protein factors.","authors":"Kamil Filipek, Sandra Blanchet, Eliza Molestak, Monika Zaciura, Colin Chih-Chien Wu, Patrycja Horbowicz-Drożdżal, Przemysław Grela, Mateusz Zalewski, Sebastian Kmiecik, Alan González-Ibarra, Dawid Krokowski, Przemysław Latoch, Agata L Starosta, Mateusz Mołoń, Yutian Shao, Lidia Borkiewicz, Barbara Michalec-Wawiórka, Leszek Wawiórka, Konrad Kubiński, Katarzyna Socała, Piotr Wlaź, Kyle W Cunningham, Rachel Green, Marina V Rodnina, Marek Tchórzewski","doi":"10.1038/s44319-024-00297-1","DOIUrl":"10.1038/s44319-024-00297-1","url":null,"abstract":"Ribosomal action is facilitated by the orchestrated work of trans-acting factors and ribosomal elements, which are subject to regulatory events, often involving phosphorylation. One such element is the ribosomal P-stalk, which plays a dual function: it activates translational GTPases, which support basic ribosomal functions, and interacts with the Gcn2 kinase, linking the ribosomes to the ISR pathway. We show that P-stalk proteins, which form a pentamer, exist in the cell exclusively in a phosphorylated state at five C-terminal domains (CTDs), ensuring optimal translation (speed and accuracy) and may play a role in the timely regulation of the Gcn2-dependent stress response. Phosphorylation of the CTD induces a structural transition from a collapsed to a coil-like structure, and the CTD gains conformational freedom, allowing specific but transient binding to various protein partners, optimizing the ribosome action. The report reveals a unique feature of the P-stalk proteins, indicating that, unlike most ribosomal proteins, which are regulated by phosphorylation in an on/off manner, the P-stalk proteins exist in a constantly phosphorylated state, which optimizes their interaction with auxiliary factors.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521373","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

Human PC4 supports telomere stability and viability in cells utilizing the alternative lengthening of telomeres mechanism. 人类 PC4 利用端粒替代性延长机制支持端粒稳定性和细胞活力。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-28 DOI: 10.1038/s44319-024-00295-3

Sara Salgado, Patricia L Abreu, Beatriz Moleirinho, Daniela S Guedes, Lee Larcombe, Claus M Azzalin

{"title":"Human PC4 supports telomere stability and viability in cells utilizing the alternative lengthening of telomeres mechanism.","authors":"Sara Salgado, Patricia L Abreu, Beatriz Moleirinho, Daniela S Guedes, Lee Larcombe, Claus M Azzalin","doi":"10.1038/s44319-024-00295-3","DOIUrl":"https://doi.org/10.1038/s44319-024-00295-3","url":null,"abstract":"Cancer cells with an activated Alternative Lengthening of Telomeres (ALT) mechanism elongate telomeres via homology-directed repair. Sustained telomeric replication stress is an essential trigger of ALT activity; however, it can lead to cell death if not properly restricted. By analyzing publicly available data from genome-wide CRISPR KO screenings, we have identified the multifunctional protein PC4 as a novel factor essential for ALT cell viability. Depletion of PC4 results in rapid ALT cell death, while telomerase-positive cells show minimal effects. PC4 depletion induces replication stress and telomere fragility primarily in ALT cells, and increases ALT activity. PC4 binds to telomeric DNA in cells, and its binding can be enhanced by telomeric replication stress. Finally, a mutant PC4 with partly impaired single stranded DNA binding activity is capable to localize to telomeres and suppress ALT activity and telomeric replication stress. We propose that PC4 supports ALT cell viability, at least partly, by averting telomere dysfunction. Further studies of PC4 interactions at ALT telomeres may hold promise for innovative therapies to eradicate ALT cancers.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521372","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