The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer.

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.

An inventory of crosstalk between ubiquitination and other post-translational modifications in orchestrating cellular processes.

Ubiquitination is an important post-translational modification (PTM) that regulates a large spectrum of cellular processes in eukaryotes. Abnormalities in ubiquitin signaling underlie numerous human pathologies including cancer and neurodegeneration. Much progress has been made during the last three decades in understanding how ubiquitin ligases recognize their substrates and how ubiquitination is orchestrated. Several mechanisms of regulation have evolved to prevent promiscuity including the assembly of ubiquitin ligases in multi-protein complexes with dedicated subunits and specific post-translational modifications of these enzymes and their co-factors. Here, we outline another layer of complexity involving the coordinated access of E3 ligases to substrates. We provide an extensive inventory of ubiquitination crosstalk with multiple PTMs including SUMOylation, phosphorylation, methylation, acetylation, hydroxylation, prolyl isomerization, PARylation, and O-GlcNAcylation. We discuss molecular mechanisms by which PTMs orchestrate ubiquitination, thus increasing its specificity as well as its crosstalk with other signaling pathways to ensure cell homeostasis.