Pub Date : 2024-06-03DOI: 10.1038/s41580-024-00738-8
Vidyani Suryadevara, Adam D Hudgins, Adarsh Rajesh, Alberto Pappalardo, Alla Karpova, Amit K Dey, Ann Hertzel, Anthony Agudelo, Azucena Rocha, Bikem Soygur, Birgit Schilling, Chase M Carver, Cristina Aguayo-Mazzucato, Darren J Baker, David A Bernlohr, Diana Jurk, Dilyana B Mangarova, Ellen M Quardokus, Elizabeth Ann L Enninga, Elizabeth L Schmidt, Feng Chen, Francesca E Duncan, Francesco Cambuli, Gagandeep Kaur, George A Kuchel, Gung Lee, Heike E Daldrup-Link, Helene Martini, Hemali Phatnani, Iman M Al-Naggar, Irfan Rahman, Jia Nie, João F Passos, Jonathan C Silverstein, Judith Campisi, Julia Wang, Kanako Iwasaki, Karina Barbosa, Kay Metis, Kerem Nernekli, Laura J Niedernhofer, Li Ding, Lichao Wang, Lisa C Adams, Liu Ruiyang, Madison L Doolittle, Marcos G Teneche, Marissa J Schafer, Ming Xu, Mohammadjavad Hajipour, Mozhgan Boroumand, Nathan Basisty, Nicholas Sloan, Nikolai Slavov, Olena Kuksenko, Paul Robson, Paul T Gomez, Periklis Vasilikos, Peter D Adams, Priscila Carapeto, Quan Zhu, Ramalakshmi Ramasamy, Rolando Perez-Lorenzo, Rong Fan, Runze Dong, Ruth R Montgomery, Sadiya Shaikh, Sanja Vickovic, Shanshan Yin, Shoukai Kang, Sonja Suvakov, Sundeep Khosla, Vesna D Garovic, Vilas Menon, Yanxin Xu, Yizhe Song, Yousin Suh, Zhixun Dou, Nicola Neretti
Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field.
{"title":"SenNet recommendations for detecting senescent cells in different tissues.","authors":"Vidyani Suryadevara, Adam D Hudgins, Adarsh Rajesh, Alberto Pappalardo, Alla Karpova, Amit K Dey, Ann Hertzel, Anthony Agudelo, Azucena Rocha, Bikem Soygur, Birgit Schilling, Chase M Carver, Cristina Aguayo-Mazzucato, Darren J Baker, David A Bernlohr, Diana Jurk, Dilyana B Mangarova, Ellen M Quardokus, Elizabeth Ann L Enninga, Elizabeth L Schmidt, Feng Chen, Francesca E Duncan, Francesco Cambuli, Gagandeep Kaur, George A Kuchel, Gung Lee, Heike E Daldrup-Link, Helene Martini, Hemali Phatnani, Iman M Al-Naggar, Irfan Rahman, Jia Nie, João F Passos, Jonathan C Silverstein, Judith Campisi, Julia Wang, Kanako Iwasaki, Karina Barbosa, Kay Metis, Kerem Nernekli, Laura J Niedernhofer, Li Ding, Lichao Wang, Lisa C Adams, Liu Ruiyang, Madison L Doolittle, Marcos G Teneche, Marissa J Schafer, Ming Xu, Mohammadjavad Hajipour, Mozhgan Boroumand, Nathan Basisty, Nicholas Sloan, Nikolai Slavov, Olena Kuksenko, Paul Robson, Paul T Gomez, Periklis Vasilikos, Peter D Adams, Priscila Carapeto, Quan Zhu, Ramalakshmi Ramasamy, Rolando Perez-Lorenzo, Rong Fan, Runze Dong, Ruth R Montgomery, Sadiya Shaikh, Sanja Vickovic, Shanshan Yin, Shoukai Kang, Sonja Suvakov, Sundeep Khosla, Vesna D Garovic, Vilas Menon, Yanxin Xu, Yizhe Song, Yousin Suh, Zhixun Dou, Nicola Neretti","doi":"10.1038/s41580-024-00738-8","DOIUrl":"10.1038/s41580-024-00738-8","url":null,"abstract":"<p><p>Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":81.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236353","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}
Pub Date : 2024-05-21DOI: 10.1038/s41580-024-00739-7
Jimena Giudice, Hao Jiang
Biomolecular condensates, sometimes also known as membraneless organelles (MLOs), can form through weak multivalent intermolecular interactions of proteins and nucleic acids, a process often associated with liquid–liquid phase separation. Biomolecular condensates are emerging as sites and regulatory platforms of vital cellular functions, including transcription and RNA processing. In the first part of this Review, we comprehensively discuss how alternative splicing regulates the formation and properties of condensates, and conversely the roles of biomolecular condensates in splicing regulation. In the second part, we focus on the spatial connection between splicing regulation and nuclear MLOs such as transcriptional condensates, splicing condensates and nuclear speckles. We then discuss key studies showing how splicing regulation through biomolecular condensates is implicated in human pathologies such as neurodegenerative diseases, different types of cancer, developmental disorders and cardiomyopathies, and conclude with a discussion of outstanding questions pertaining to the roles of condensates and MLOs in splicing regulation and how to experimentally study them. Biomolecular condensates are emerging as hubs of splicing regulation. This Review discusses the modulation of condensate functions through alternative splicing, regulation of (co-transcriptional) splicing at condensates and the involvement of these condensates in human diseases.
{"title":"Splicing regulation through biomolecular condensates and membraneless organelles","authors":"Jimena Giudice, Hao Jiang","doi":"10.1038/s41580-024-00739-7","DOIUrl":"10.1038/s41580-024-00739-7","url":null,"abstract":"Biomolecular condensates, sometimes also known as membraneless organelles (MLOs), can form through weak multivalent intermolecular interactions of proteins and nucleic acids, a process often associated with liquid–liquid phase separation. Biomolecular condensates are emerging as sites and regulatory platforms of vital cellular functions, including transcription and RNA processing. In the first part of this Review, we comprehensively discuss how alternative splicing regulates the formation and properties of condensates, and conversely the roles of biomolecular condensates in splicing regulation. In the second part, we focus on the spatial connection between splicing regulation and nuclear MLOs such as transcriptional condensates, splicing condensates and nuclear speckles. We then discuss key studies showing how splicing regulation through biomolecular condensates is implicated in human pathologies such as neurodegenerative diseases, different types of cancer, developmental disorders and cardiomyopathies, and conclude with a discussion of outstanding questions pertaining to the roles of condensates and MLOs in splicing regulation and how to experimentally study them. Biomolecular condensates are emerging as hubs of splicing regulation. This Review discusses the modulation of condensate functions through alternative splicing, regulation of (co-transcriptional) splicing at condensates and the involvement of these condensates in human diseases.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":81.3,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141073909","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}
Pub Date : 2024-05-17DOI: 10.1038/s41580-024-00747-7
Esther M. Verheyen, Cara J. Gottardi
Verheyen and Gottardi revisit two seminal papers by the Basler, Peifer and Clevers labs elucidating the role of nuclear β-catenin in Wnt signal transduction through its interaction with TCF at Wnt target genes.
{"title":"Solving the Wnt nuclear puzzle","authors":"Esther M. Verheyen, Cara J. Gottardi","doi":"10.1038/s41580-024-00747-7","DOIUrl":"10.1038/s41580-024-00747-7","url":null,"abstract":"Verheyen and Gottardi revisit two seminal papers by the Basler, Peifer and Clevers labs elucidating the role of nuclear β-catenin in Wnt signal transduction through its interaction with TCF at Wnt target genes.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":81.3,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953674","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}
Pub Date : 2024-05-13DOI: 10.1038/s41580-024-00744-w
Fereshteh Sadat Younesi, Andrew E. Miller, Thomas H. Barker, Fabio M. V. Rossi, Boris Hinz
{"title":"Author Correction: Fibroblast and myofibroblast activation in normal tissue repair and fibrosis","authors":"Fereshteh Sadat Younesi, Andrew E. Miller, Thomas H. Barker, Fabio M. V. Rossi, Boris Hinz","doi":"10.1038/s41580-024-00744-w","DOIUrl":"10.1038/s41580-024-00744-w","url":null,"abstract":"","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":81.3,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41580-024-00744-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916622","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}
Pub Date : 2024-05-10DOI: 10.1038/s41580-024-00743-x
Eytan Zlotorynski
Cleavage of promoter-upstream antisense RNAs by the Integrator complex supports the preferential transcription of pre-mRNAs.
Integrator 复合物对启动子-上游反义 RNA 的裂解支持 pre-mRNA 的优先转录。
{"title":"Integrator and U1 snRNPs steer Pol II in the right direction","authors":"Eytan Zlotorynski","doi":"10.1038/s41580-024-00743-x","DOIUrl":"10.1038/s41580-024-00743-x","url":null,"abstract":"Cleavage of promoter-upstream antisense RNAs by the Integrator complex supports the preferential transcription of pre-mRNAs.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":112.7,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904429","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}
Pub Date : 2024-05-02DOI: 10.1038/s41580-024-00740-0
Claire S. Durrant
Claire Durrant reminds us of the importance of studying the physiological roles of proteins and their aggregates to understand their roles in disease and inform therapies, discussing a 2008 paper on amyloid-β from the Arancio lab.
{"title":"Is amyloid-β a friend or foe?","authors":"Claire S. Durrant","doi":"10.1038/s41580-024-00740-0","DOIUrl":"10.1038/s41580-024-00740-0","url":null,"abstract":"Claire Durrant reminds us of the importance of studying the physiological roles of proteins and their aggregates to understand their roles in disease and inform therapies, discussing a 2008 paper on amyloid-β from the Arancio lab.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":81.3,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819422","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}
Pub Date : 2024-05-02DOI: 10.1038/s41580-024-00741-z
Stephanie L. Moon
Stephanie Moon discusses findings that revealed that ribosome stalling can lead to the suppression of translation initiation in the brain, delaying the onset of neurodegeneration.
{"title":"Translation feedback control in the brain","authors":"Stephanie L. Moon","doi":"10.1038/s41580-024-00741-z","DOIUrl":"10.1038/s41580-024-00741-z","url":null,"abstract":"Stephanie Moon discusses findings that revealed that ribosome stalling can lead to the suppression of translation initiation in the brain, delaying the onset of neurodegeneration.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":81.3,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819498","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}
Pub Date : 2024-04-30DOI: 10.1038/s41580-024-00730-2
Helmut Sies, Ryan J. Mailloux, Ursula Jakob
Oxidation–reduction (redox) reactions are central to the existence of life. Reactive species of oxygen, nitrogen and sulfur mediate redox control of a wide range of essential cellular processes. Yet, excessive levels of oxidants are associated with ageing and many diseases, including cardiological and neurodegenerative diseases, and cancer. Hence, maintaining the fine-tuned steady-state balance of reactive species production and removal is essential. Here, we discuss new insights into the dynamic maintenance of redox homeostasis (that is, redox homeodynamics) and the principles underlying biological redox organization, termed the ‘redox code’. We survey how redox changes result in stress responses by hormesis mechanisms, and how the lifelong cumulative exposure to environmental agents, termed the ‘exposome’, is communicated to cells through redox signals. Better understanding of the molecular and cellular basis of redox biology will guide novel redox medicine approaches aimed at preventing and treating diseases associated with disturbed redox regulation. Oxidation–reduction (redox) reactions involving reactive oxygen, nitrogen and sulfur species are vital for life, but excessive oxidant levels contribute to ageing and diseases. This Review explores cellular dynamics of redox homeostasis, such as responses to oxidative and reductive stresses and intracellular and intercellular redox communication pathways.
{"title":"Fundamentals of redox regulation in biology","authors":"Helmut Sies, Ryan J. Mailloux, Ursula Jakob","doi":"10.1038/s41580-024-00730-2","DOIUrl":"10.1038/s41580-024-00730-2","url":null,"abstract":"Oxidation–reduction (redox) reactions are central to the existence of life. Reactive species of oxygen, nitrogen and sulfur mediate redox control of a wide range of essential cellular processes. Yet, excessive levels of oxidants are associated with ageing and many diseases, including cardiological and neurodegenerative diseases, and cancer. Hence, maintaining the fine-tuned steady-state balance of reactive species production and removal is essential. Here, we discuss new insights into the dynamic maintenance of redox homeostasis (that is, redox homeodynamics) and the principles underlying biological redox organization, termed the ‘redox code’. We survey how redox changes result in stress responses by hormesis mechanisms, and how the lifelong cumulative exposure to environmental agents, termed the ‘exposome’, is communicated to cells through redox signals. Better understanding of the molecular and cellular basis of redox biology will guide novel redox medicine approaches aimed at preventing and treating diseases associated with disturbed redox regulation. Oxidation–reduction (redox) reactions involving reactive oxygen, nitrogen and sulfur species are vital for life, but excessive oxidant levels contribute to ageing and diseases. This Review explores cellular dynamics of redox homeostasis, such as responses to oxidative and reductive stresses and intracellular and intercellular redox communication pathways.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":81.3,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140818038","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}
Pub Date : 2024-04-29DOI: 10.1038/s41580-024-00729-9
Jonathan M. Tsai, Radosław P. Nowak, Benjamin L. Ebert, Eric S. Fischer
Targeted protein degradation refers to the use of small molecules to induce the selective degradation of proteins. In its most common form, this degradation is achieved through ligand-mediated neo-interactions between ubiquitin E3 ligases — the principal waste disposal machines of a cell — and the protein targets of interest, resulting in ubiquitylation and subsequent proteasomal degradation. Notable advances have been made in biological and mechanistic understanding of serendipitously discovered degraders. This improved understanding and novel chemistry has not only provided clinical proof of concept for targeted protein degradation but has also led to rapid growth of the field, with dozens of investigational drugs in active clinical trials. Two distinct classes of protein degradation therapeutics are being widely explored: bifunctional PROTACs and molecular glue degraders, both of which have their unique advantages and challenges. Here, we review the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. We also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take. This article reviews the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. The authors also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take.
{"title":"Targeted protein degradation: from mechanisms to clinic","authors":"Jonathan M. Tsai, Radosław P. Nowak, Benjamin L. Ebert, Eric S. Fischer","doi":"10.1038/s41580-024-00729-9","DOIUrl":"10.1038/s41580-024-00729-9","url":null,"abstract":"Targeted protein degradation refers to the use of small molecules to induce the selective degradation of proteins. In its most common form, this degradation is achieved through ligand-mediated neo-interactions between ubiquitin E3 ligases — the principal waste disposal machines of a cell — and the protein targets of interest, resulting in ubiquitylation and subsequent proteasomal degradation. Notable advances have been made in biological and mechanistic understanding of serendipitously discovered degraders. This improved understanding and novel chemistry has not only provided clinical proof of concept for targeted protein degradation but has also led to rapid growth of the field, with dozens of investigational drugs in active clinical trials. Two distinct classes of protein degradation therapeutics are being widely explored: bifunctional PROTACs and molecular glue degraders, both of which have their unique advantages and challenges. Here, we review the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. We also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take. This article reviews the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. The authors also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":81.3,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140808341","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}
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