USP22, an hSAGA subunit and potential cancer stem cell marker, reverses the polycomb-catalyzed ubiquitylation of histone H2A
USP22, an hSAGA subunit and potential cancer stem cell marker, reverses the polycomb-catalyzed ubiquitylation of histone H2A
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DOI：
10.4161/cc.7.11.5962
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发表时间：
2008-06-01
期刊：
影响因子：
4.3
通讯作者：
McMahon, Steven B.
中科院分区：
文献类型：
--
作者：
Zhang, Xiao-Yong;Pfeiffer, Harla K.;McMahon, Steven B.
对哺乳动物hSAGA转录辅激活因子复合物的初步研究确定乙酰转移酶hGCN 5/PCAF为唯一已知的酶亚基。最近，我们和其他人证明了泛素水解酶USP 22包含hSAGA的第二个酶亚基，这是激活子驱动的转录所需的。USP 22与多梳泛素连接酶一起表达在定义治疗抗性肿瘤的11个基因签名中。在生物化学水平上，这些Polycomb蛋白通过催化组蛋白H2 A的泛素化而作为全局转录抑制因子发挥作用。在酵母中，USP 22同源物通过从不同的核心组蛋白H2 B去除泛素而作为转录辅激活因子发挥功能。考虑到USP 22在癌症中作为11个基因签名的一部分表达，该基因签名包括使H2 A泛素化的转录阻遏物，因此似乎USP 22可能部分地通过该相同底物的去泛素化来激活转录。如本文所报道的，USP 22的底物特异性的生物化学分析显示，除了H2 B之外，它还使组蛋白H2 A去泛素化。这一发现支持了一种模型，其中H2 A泛素水解酶USP 22与Polycomb H2 A泛素连接酶协同表达，以便在Polycomb介导的全局抑制下维持某些关键转化基因的转录。
Initial studies of the mammalian hSAGA transcriptional coactivator complex identified the acetyltransferase hGCN5/PCAF as the only known enzymatic subunit. Recently we and others demonstrated that the ubiquitin hydrolase USP22 comprises a second enzymatic subunit of hSAGA, which is required for activator-driven transcription. USP22 is expressed with polycomb ubiquitin ligases in an 11 gene signature that defines therapy-resistant tumors. At the biochemical level, these Polycomb proteins function as global transcriptional repressors by catalyzing the ubiquitylation of histone H2A. In yeast, the USP22 homolog functions as a transcriptional coactivator by removing ubiquitin from a distinct core histones, H2B. Given that USP22 is expressed in cancer as part of an 11 gene signature that includes transcriptional repressors which ubiquitylate H2A, it seemed possible that USP22 might activate transcription in part via the deubiquitylation of this same substrate. As reported here, biochemical analysis of the substrate specificity of USP22 reveals that it deubiquitylates histone H2A in addition to H2B. This finding supports a model in which the H2A ubiquitin hydrolase USP22 is coordinately expressed with Polycomb H2A ubiquitin ligases in order that the transcription of certain critical transforming genes be maintained in the face of the global repression mediated by Polycomb.