A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells
Summary: Polycomb repressive complex 2 (PRC2), composed of the core subunits EED, SUZ12, and either EZH1 or EZH2, is critical for maintaining cellular identity in multicellular organisms. PRC2 deposits H3K27me3, which is thought to recruit the canonical form of PRC1 (cPRC1) to promote gene repressio...
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Elsevier
2025-01-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724015432 |
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| author | Rachel McCole James Nolan David M. Reck Craig Monger Samantha Rustichelli Eric Conway Gerard L. Brien Cheng Wang Orla Deevy Hannah K. Neikes Frances M. Bashore Aoibhinn Mooney Richard Flavin Elisabeth Vandenberghe Sarena F. Flanigan Diego Pasini Chen Davidovich Michiel Vermeulen Lindsey I. James Evan Healy Adrian P. Bracken |
| author_facet | Rachel McCole James Nolan David M. Reck Craig Monger Samantha Rustichelli Eric Conway Gerard L. Brien Cheng Wang Orla Deevy Hannah K. Neikes Frances M. Bashore Aoibhinn Mooney Richard Flavin Elisabeth Vandenberghe Sarena F. Flanigan Diego Pasini Chen Davidovich Michiel Vermeulen Lindsey I. James Evan Healy Adrian P. Bracken |
| author_sort | Rachel McCole |
| collection | DOAJ |
| description | Summary: Polycomb repressive complex 2 (PRC2), composed of the core subunits EED, SUZ12, and either EZH1 or EZH2, is critical for maintaining cellular identity in multicellular organisms. PRC2 deposits H3K27me3, which is thought to recruit the canonical form of PRC1 (cPRC1) to promote gene repression. Here, we show that EZH1-PRC2 and cPRC1 are the primary Polycomb complexes on target genes in non-dividing, quiescent cells. Furthermore, these cells are resistant to PRC2 inhibitors. While PROTAC-mediated degradation of EZH1-PRC2 in quiescent cells does not reduce H3K27me3, it partially displaces cPRC1. Our results reveal an evolutionarily conserved switch to less catalytically active Polycomb complexes in non-dividing cells and raise concerns about using PRC2 inhibitors in cancers with significant populations of non-dividing cells. |
| format | Article |
| id | doaj-art-d34e3ad7aa9f4e7dabf355777b124444 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-d34e3ad7aa9f4e7dabf355777b1244442025-01-13T04:18:46ZengElsevierCell Reports2211-12472025-01-01441115192A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cellsRachel McCole0James Nolan1David M. Reck2Craig Monger3Samantha Rustichelli4Eric Conway5Gerard L. Brien6Cheng Wang7Orla Deevy8Hannah K. Neikes9Frances M. Bashore10Aoibhinn Mooney11Richard Flavin12Elisabeth Vandenberghe13Sarena F. Flanigan14Diego Pasini15Chen Davidovich16Michiel Vermeulen17Lindsey I. James18Evan Healy19Adrian P. Bracken20Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, IrelandSmurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Department of Haematology, St. James’ Hospital, Dublin 8, IrelandSmurfit Institute of Genetics, Trinity College Dublin, Dublin 2, IrelandSmurfit Institute of Genetics, Trinity College Dublin, Dublin 2, IrelandIEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Via Adamello 16, 20139 Milan, ItalySmurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, IrelandCancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UKSmurfit Institute of Genetics, Trinity College Dublin, Dublin 2, IrelandSmurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, IrelandDepartment of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the NetherlandsCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Histopathology, St. James’ Hospital, Dublin 8, Ireland; Department of Histopathology, Trinity College Dublin, Dublin 2, IrelandDepartment of Histopathology, St. James’ Hospital, Dublin 8, Ireland; Department of Histopathology, Trinity College Dublin, Dublin 2, IrelandDepartment of Haematology, St. James’ Hospital, Dublin 8, IrelandDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, AustraliaIEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Via Adamello 16, 20139 Milan, Italy; Department of Health Sciences, University of Milan, Via A. di Rudini 8, 20142 Milan, ItalyDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia; EMBL-Australia, Clayton, VIC, AustraliaDepartment of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands; Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the NetherlandsCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USASmurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia; Corresponding authorSmurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Corresponding authorSummary: Polycomb repressive complex 2 (PRC2), composed of the core subunits EED, SUZ12, and either EZH1 or EZH2, is critical for maintaining cellular identity in multicellular organisms. PRC2 deposits H3K27me3, which is thought to recruit the canonical form of PRC1 (cPRC1) to promote gene repression. Here, we show that EZH1-PRC2 and cPRC1 are the primary Polycomb complexes on target genes in non-dividing, quiescent cells. Furthermore, these cells are resistant to PRC2 inhibitors. While PROTAC-mediated degradation of EZH1-PRC2 in quiescent cells does not reduce H3K27me3, it partially displaces cPRC1. Our results reveal an evolutionarily conserved switch to less catalytically active Polycomb complexes in non-dividing cells and raise concerns about using PRC2 inhibitors in cancers with significant populations of non-dividing cells.http://www.sciencedirect.com/science/article/pii/S2211124724015432CP: Molecular biology |
| spellingShingle | Rachel McCole James Nolan David M. Reck Craig Monger Samantha Rustichelli Eric Conway Gerard L. Brien Cheng Wang Orla Deevy Hannah K. Neikes Frances M. Bashore Aoibhinn Mooney Richard Flavin Elisabeth Vandenberghe Sarena F. Flanigan Diego Pasini Chen Davidovich Michiel Vermeulen Lindsey I. James Evan Healy Adrian P. Bracken A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells Cell Reports CP: Molecular biology |
| title | A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells |
| title_full | A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells |
| title_fullStr | A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells |
| title_full_unstemmed | A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells |
| title_short | A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells |
| title_sort | conserved switch to less catalytically active polycomb repressive complexes in non dividing cells |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724015432 |
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