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. 2025 Jan 28;44(1):115192.
doi: 10.1016/j.celrep.2024.115192. Epub 2025 Jan 11.

A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells

Rachel McCole  1 , James Nolan  2 , David M Reck  1 , Craig Monger  1 , Samantha Rustichelli  3 , Eric Conway  4 , Gerard L Brien  5 , Cheng Wang  1 , Orla Deevy  4 , Hannah K Neikes  6 , Frances M Bashore  7 , Aoibhinn Mooney  8 , Richard Flavin  8 , Elisabeth Vandenberghe  9 , Sarena F Flanigan  10 , Diego Pasini  11 , Chen Davidovich  12 , Michiel Vermeulen  13 , Lindsey I James  14 , Evan Healy  15 , Adrian P Bracken  16
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A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells

Rachel McCole et al. Cell Rep. .

Abstract

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.

Keywords: CBX7; CP: Molecular biology; EED; EZH1; EZH2; H3K27me3; PRC1; PRC2; PROTAC; Polycomb; cellular quiescence.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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