Cancer Research UK, London Research Institute, London, UK.
EMBO J. 2010 Aug 4;29(15):2553-65. doi: 10.1038/emboj.2010.129. Epub 2010 Jul 2.
An important facet of transcriptional repression by Polycomb repressive complex 1 (PRC1) is the mono-ubiquitination of histone H2A by the combined action of the Posterior sex combs (Psc) and Sex combs extra (Sce) proteins. Here, we report that two ubiquitin-specific proteases, USP7 and USP11, co-purify with human PRC1-type complexes through direct interactions with the Psc orthologues MEL18 and BMI1, and with other PRC1 components. Ablation of either USP7 or USP11 in primary human fibroblasts results in de-repression of the INK4a tumour suppressor accompanied by loss of PRC1 binding at the locus and a senescence-like proliferative arrest. Mechanistically, USP7 and USP11 regulate the ubiquitination status of the Psc and Sce proteins themselves, thereby affecting their turnover and abundance. Our results point to a novel function for USPs in the regulation and function of Polycomb complexes.
多梳抑制复合物 1 (PRC1) 转录抑制的一个重要方面是通过后性梳 (Psc) 和性梳额外 (Sce) 蛋白的联合作用对组蛋白 H2A 的单泛素化。在这里，我们报告说，两种泛素特异性蛋白酶，USP7 和 USP11，通过与 Psc 同源物 MEL18 和 BMI1 以及其他 PRC1 成分的直接相互作用，与人类 PRC1 型复合物共纯化。在原代人成纤维细胞中敲除 USP7 或 USP11 会导致 INK4a 肿瘤抑制因子去抑制，同时伴随着该基因座上 PRC1 结合的丧失和衰老样增殖停滞。在机制上，USP7 和 USP11 调节 Psc 和 Sce 蛋白自身的泛素化状态，从而影响它们的周转和丰度。我们的结果指出了 USPs 在多梳复合物的调节和功能中的新作用。
