Cell Reports (Jan 2025)
A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells
- 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
Affiliations
- Rachel McCole
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
- James Nolan
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Department of Haematology, St. James’ Hospital, Dublin 8, Ireland
- David M. Reck
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
- Craig Monger
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
- Samantha Rustichelli
- IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Via Adamello 16, 20139 Milan, Italy
- Eric Conway
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland
- Gerard L. Brien
- Cancer 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, UK
- Cheng Wang
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
- Orla Deevy
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland
- Hannah K. Neikes
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands
- Frances M. Bashore
- Center 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
- Aoibhinn Mooney
- Department of Histopathology, St. James’ Hospital, Dublin 8, Ireland; Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland
- Richard Flavin
- Department of Histopathology, St. James’ Hospital, Dublin 8, Ireland; Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland
- Elisabeth Vandenberghe
- Department of Haematology, St. James’ Hospital, Dublin 8, Ireland
- Sarena F. Flanigan
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
- Diego Pasini
- IEO, 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, Italy
- Chen Davidovich
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia; EMBL-Australia, Clayton, VIC, Australia
- Michiel Vermeulen
- Department 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 Netherlands
- Lindsey I. James
- Center 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, USA
- Evan Healy
- Smurfit 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 author
- Adrian P. Bracken
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Corresponding author
- Journal volume & issue
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Vol. 44,
no. 1
p. 115192
Abstract
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.
