A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells
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.
Authors
- Aoibhinn Mooney
- Adrian P. Bracken (ORCID: https://orcid.org/0000-0002-1547-9443)
- Richard Flavin (ORCID: https://orcid.org/0000-0002-4993-4563)
- Craig Monger (ORCID: https://orcid.org/0000-0002-8059-5299)
- Eric Conway (ORCID: https://orcid.org/0000-0001-5591-3083)
- Chen Davidovich
- Samantha Rustichelli (ORCID: https://orcid.org/0000-0002-7156-9494)
- Frances M. Bashore (ORCID: https://orcid.org/0000-0003-4241-9873)
- Orla Deevy (ORCID: https://orcid.org/0000-0002-6422-843X)
- Rachel McCole
- Gerard L. Brien (ORCID: https://orcid.org/0000-0003-4275-7178)
- Diego Pasini (ORCID: https://orcid.org/0000-0002-9879-6486)
- Evan Healy (ORCID: https://orcid.org/0000-0001-7956-7242)
- Hannah K. Neikes
- Michiel Vermeulen (ORCID: https://orcid.org/0000-0003-0836-6894)
- Lindsey Ingerman James (ORCID: https://orcid.org/0000-0002-6034-7116)
- Elisabeth Vandenberghe (ORCID: https://orcid.org/0000-0002-7731-9437)
- Sarena F. Flanigan
- David M Reck (ORCID: https://orcid.org/0009-0000-3862-8440)
- Cheng Wang (ORCID: https://orcid.org/0000-0001-7886-2143)
- James Nolan (ORCID: https://orcid.org/0000-0001-6442-496X)
Institutions
- University of North Carolina at Chapel Hill (US)
- Radboud University Nijmegen (NL)
- Trinity College Dublin (IE)
- Discovery Institute (US)
- Australian Regenerative Medicine Institute (AU)
- Edinburgh Cancer Research (GB)
- Radboud University Medical Center (NL)
- Radboud Institute for Molecular Life Sciences (NL)
- Oncode Institute (NL)
- St. James's Hospital (IE)
- Monash University (AU)
- European Institute of Oncology (IT)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.115192
- Citations
- 10
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- Wellcome Trust
- EMBL Australia
- Science Foundation Ireland
- University College Dublin
- Irish Research Council
- Oncode Institute
- National Institutes of Health
- National Health and Medical Research Council
- National Institute on Drug Abuse