ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth.
ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth.
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DOI：
10.1016/j.molcel.2016.03.030
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发表时间：
2016-05-19
期刊：
影响因子：
16
通讯作者：
Dent SY
中科院分区：
文献类型：
--
作者：
Atanassov BS;Mohan RD;Lan X;Kuang X;Lu Y;Lin K;McIvor E;Li W;Zhang Y;Florens L;Byrum SD;Mackintosh SG;Calhoun-Davis T;Koutelou E;Wang L;Tang DG;Tackett AJ;Washburn MP;Workman JL;Dent SY
组蛋白H2B单泛素化（H2Bub1）主要参与基因调控。佐贺复合物的去泛素化模块（DUBm）是全球H2Bub1水平的主要调节因子，该DUBm的组分与神经退行性疾病和癌症有关。出乎意料的是，我们发现DUBm的酶中心USP22的消融导致全球H2bub1水平的降低，而不是增加。相反，非酶组分ATXN7L3或ENY2的消耗导致H2Bub1增加。这些观察使我们发现了两个新的H2Bub1 DUB，USP 27X和USP 51，它们独立于佐贺发挥作用，并与USP 22竞争ATXN7L3和ENY 2的活性。与USP 22一样，USP 51和USP 27 X是正常细胞增殖所必需的，它们的消耗抑制肿瘤生长。我们的研究结果表明，ATXN7L3和ENY2协调多种去泛素化酶的活动，这些活动的不平衡可能会增强包括癌症在内的人类疾病。
Histone H2B monoubiquitination (H2Bub1) is centrally involved in gene regulation. The deubiquitination module (DUBm) of the SAGA complex is a major regulator of global H2Bub1 levels, and components of this DUBm are linked to both neurodegenerative diseases and cancer. Unexpectedly, we find that ablation of USP22, the enzymatic center of the DUBm, leads to a reduction, rather than an increase, in global H2bub1 levels. In contrast, depletion of non-enzymatic components, ATXN7L3 or ENY2, results in increased H2Bub1. These observations led us to discover two new H2Bub1 DUBs, USP27X and USP51, which function independently of SAGA and which compete with USP22 for ATXN7L3 and ENY2 for activity. Like USP22, USP51 and USP27X are required for normal cell proliferation, and their depletion suppresses tumor growth. Our results reveal that ATXN7L3 and ENY2 orchestrate activities of multiple deubiquitinating enzymes and that imbalances in these activities likely potentiate human diseases including cancer.