title: The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer.
abstract: The deubiquitinase (DUB) and tumor suppressor BAP1 catalyzes ubiquitin removal from histone H2A Lys-119 and coordinates cell proliferation, but how BAP1 partners modulate its function remains poorly understood. Here, we report that BAP1 forms two mutually exclusive complexes with the transcriptional regulators ASXL1 and ASXL2, which are necessary for maintaining proper protein levels of this DUB. Conversely, BAP1 is essential for maintaining ASXL2, but not ASXL1, protein stability. Notably, cancer-associated loss of BAP1 expression results in ASXL2 destabilization and hence loss of its function. ASXL1 and ASXL2 use their ASXM domains to interact with the C-terminal domain (CTD) of BAP1, and these interactions are required for ubiquitin binding and H2A deubiquitination. The deubiquitination-promoting effect of ASXM requires intramolecular interactions between catalytic and non-catalytic domains of BAP1, which generate a composite ubiquitin-binding interface (CUBI). Notably, the CUBI engages multiple interactions with ubiquitin involving (i) the ubiquitin carboxyl hydrolase catalytic domain of BAP1, which interacts with the hydrophobic patch of ubiquitin, and (ii) the CTD domain, which interacts with a charged patch of ubiquitin. Significantly, we identified cancer-associated mutations of BAP1 that disrupt the CUBI and notably an in-frame deletion in the CTD that inhibits its interaction with ASXL1/2 and DUB activity and deregulates cell proliferation. Moreover, we demonstrated that BAP1 interaction with ASXL2 regulates cell senescence and that ASXL2 cancer-associated mutations disrupt BAP1 DUB activity. Thus, inactivation of the BAP1/ASXL2 axis might contribute to cancer development.
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Salima
authors.initials: S
authors.lastname: Daou
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Ian
authors.initials: I
authors.lastname: Hammond-Martel
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Nazar
authors.initials: N
authors.lastname: Mashtalir
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Haithem
authors.initials: H
authors.lastname: Barbour
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gagnon
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Nicholas V G
authors.initials: NV
authors.lastname: Iannantuono
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Nadine Sen
authors.initials: NS
authors.lastname: Nkwe
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Alena
authors.initials: A
authors.lastname: Motorina
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Helen
authors.initials: H
authors.lastname: Pak
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Helen
authors.initials: H
authors.lastname: Yu
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Hugo
authors.initials: H
authors.lastname: Wurtele
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Eric
authors.initials: E
authors.lastname: Milot
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and.
authors.forename: Frédérick A
authors.initials: FA
authors.lastname: Mallette
authors.affiliation: the Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813.
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
authors.affiliation: From the Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada and aelbachir.hmr@ssss.gouv.qc.ca.
authors.forename: El Bachir
authors.initials: el B
authors.lastname: Affar
mesh_terms: D049109:Cell Proliferation; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*
chemical_list: C473949:ASXL1 protein, human; C484295:ASXL2 protein, human; C400134:BAP1 protein, human; D006657:Histones; D046912:Multiprotein Complexes; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases
keywords: ASXL; BAP1; Calypso; Polycomb Group Proteins; cancer biology; cell proliferation; cellular senescence; deubiquitylation (deubiquitination); epigenetics; histone H2A ubiquitination