Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.
Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.
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多梳族（Polycomb group，PcG）蛋白是一种转录抑制因子，控制着从动物细胞命运决定和干细胞多能性的维持到植物开花时间的控制等过程。在果蝇中，遗传研究确定了超过15种不同的PcG蛋白，这些蛋白是抑制细胞中同源异型（HOX）和其他发育调节基因所必需的，在这些基因必须保持不活动。生化分析表明，这些PcG蛋白存在于不同的多蛋白复合物中，结合并修饰靶基因的染色质。其中，Polycomb阻遏复合物1（PRC 1）和相关的dRing相关因子（dRAF）复合物含有用于组蛋白H2 A的单泛素化的E3连接酶活性（参考文献）。在这里，我们表明，未表征的果蝇PcG基因calypso编码的泛素羧基末端水解酶BAP 1。生物化学纯化的Calypso与PcG蛋白ASX形成复合物，这种复合物被称为Polycomb抑制性去泛素化酶（PR-DUB），与果蝇中的PcG靶基因结合。重构的重组果蝇和人PR-DUB复合物从核小体中的H2 A而不是H2 B中去除monoubiquitin。缺乏PR-DUB的果蝇突变体显示monoubiquitinated H2 A水平的强烈增加。破坏Calypso催化活性的突变或ASX亚基的缺失在体外消除H2 A去泛素化，在体内消除HOX基因抑制。因此，Polycomb基因沉默可能需要PRC 1和dRAF的H2 A泛素化与PR-DUB的H2 A去泛素化之间的动态平衡。
Polycomb group (PcG) proteins are transcriptional repressors that control processes ranging from the maintenance of cell fate decisions and stem cell pluripotency in animals to the control of flowering time in plants. In Drosophila, genetic studies identified more than 15 different PcG proteins that are required to repress homeotic (HOX) and other developmental regulator genes in cells where they must stay inactive. Biochemical analyses established that these PcG proteins exist in distinct multiprotein complexes that bind to and modify chromatin of target genes. Among those, Polycomb repressive complex 1 (PRC1) and the related dRing-associated factors (dRAF) complex contain an E3 ligase activity for monoubiquitination of histone H2A (refs). Here we show that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1. Biochemically purified Calypso exists in a complex with the PcG protein ASX, and this complex, named Polycomb repressive deubiquitinase (PR-DUB), is bound at PcG target genes in Drosophila. Reconstituted recombinant Drosophila and human PR-DUB complexes remove monoubiquitin from H2A but not from H2B in nucleosomes. Drosophila mutants lacking PR-DUB show a strong increase in the levels of monoubiquitinated H2A. A mutation that disrupts the catalytic activity of Calypso, or absence of the ASX subunit abolishes H2A deubiquitination in vitro and HOX gene repression in vivo. Polycomb gene silencing may thus entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H2A deubiquitination by PR-DUB.
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