In Drosophila, a complex consisting of Calypso and ASX catalyzes H2A deubiquitination and has been reported to act as part of the Polycomb machinery in transcriptional silencing. The mammalian homologs of these proteins (BAP1 and ASXL1/2/3, respectively), are frequently mutated in various cancer types, yet their precise functions remain unclear. Using an integrative approach based on isogenic cell lines generated with CRISPR/Cas9, we uncover an unanticipated role for BAP1 in gene activation. This function requires the assembly of an enzymatically active BAP1-associated core complex (BAP1.com) containing one of the redundant ASXL proteins. We investigate the mechanism underlying BAP1.com-mediated transcriptional regulation and show that it does not participate in Polycomb-mediated silencing. Instead, our results establish that the function of BAP1.com is to safeguard transcriptionally active genes against silencing by the Polycomb Repressive Complex 1.

中文翻译：

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BAP1复合物通过相反的PRC1介导的H2A泛素化促进转录

在果蝇中，由Calypso和ASX组成的复合物催化H2A去泛素化，据报道在转录沉默中它是Polycomb机制的一部分。这些蛋白质的哺乳动物同源物（分别为BAP1和ASXL1 / 2/3）在各种癌症类型中经常发生突变，但其确切功能仍不清楚。使用基于由CRISPR / Cas9生成的同基因细胞系的整合方法，我们发现了BAP1在基因激活中的意外作用。此功能需要组装包含一种冗余ASXL蛋白的酶促活性BAP1相关核心复合体（BAP1.com）。我们调查了BAP1.com介导的转录调控的基础机制，并表明它不参与Polycomb介导的沉默。相反，我们的结果确定了BAP1的功能。