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Abstract
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.
In Drosophila, the Calypso–ASX complex catalyzes H2A deubiquitination and aids Polycomb in transcriptional silencing. Here the authors show that the orthologous complex, BAP1.com, promotes gene activation by counteracting PRC1-mediated gene silencing.
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1 Paris Sciences et Lettres Research University, Sorbonne University, Institut Curie, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657) ; INSERM U934/CNRS UMR3215, Paris, France (GRID:grid.462844.8)
2 Paris Sciences et Lettres Research University, Sorbonne University, Institut Curie, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657) ; INSERM U934/CNRS UMR3215, Paris, France (GRID:grid.462844.8) ; INSERM U900, Mines ParisTech, Paris, France (GRID:grid.58140.38) (ISNI:0000 0001 2097 6957)
3 Paris Sciences et Lettres Research University, Sorbonne University, Institut Curie, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657)
4 Helmholtz Zentrum München, Institute of Functional Epigenetics, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525)
5 Paris Sciences et Lettres Research University, Sorbonne University, Institut Curie, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657) ; INSERM U900, Mines ParisTech, Paris, France (GRID:grid.58140.38) (ISNI:0000 0001 2097 6957)
6 University of Paris Descartes, Department of Molecular Genetics Pathology, Cochin Hospital, HUPC AP-HP, EA7331, Faculty of Pharmacy, Paris, France (GRID:grid.10992.33) (ISNI:0000 0001 2188 0914)
7 Université Paris-Saclay, Département d’Innovation Thérapeutique et Essais Précoces, INSERM U981, Gustave Roussy, Villejuif, France (GRID:grid.460789.4) (ISNI:0000 0004 4910 6535)