在非分裂细胞中向催化活性较低的多梳抑制复合物的保守转变。
A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells.
作者信息
McCole Rachel, Nolan James, Reck David M, Monger Craig, Rustichelli Samantha, Conway Eric, Brien Gerard L, Wang Cheng, Deevy Orla, Neikes Hannah K, Bashore Frances M, Mooney Aoibhinn, Flavin Richard, Vandenberghe Elisabeth, Flanigan Sarena F, Pasini Diego, Davidovich Chen, Vermeulen Michiel, James Lindsey I, Healy Evan, Bracken Adrian P
机构信息
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; Department of Haematology, St. James' Hospital, Dublin 8, Ireland.
出版信息
Cell Rep. 2025 Jan 28;44(1):115192. doi: 10.1016/j.celrep.2024.115192. Epub 2025 Jan 11.
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.
多梳抑制复合物2（PRC2）由核心亚基EED、SUZ12以及EZH1或EZH2组成，对维持多细胞生物中的细胞特性至关重要。PRC2沉积H3K27me3，人们认为它会招募经典形式的PRC1（cPRC1）来促进基因抑制。在这里，我们表明EZH1-PRC2和cPRC1是处于非分裂静止细胞中靶基因上的主要多梳复合物。此外，这些细胞对PRC2抑制剂具有抗性。虽然PROTAC介导的静止细胞中EZH1-PRC2的降解不会降低H3K27me3，但它会部分取代cPRC1。我们的结果揭示了在非分裂细胞中向催化活性较低的多梳复合物的进化保守转变，并引发了对在具有大量非分裂细胞群体的癌症中使用PRC2抑制剂的担忧。
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