Figure 1.

BAP1 nuclear and cytoplasmic physiologic activities. BAP1 nuclear activities (top). BAP1 stabilizes and recruits INO80 to replication forks, via the interaction with H2A-Ub, for efficient replication fork progression and DNA replication, thereby ensuring genome stability (21, 22). Nuclear BAP1 regulates gene expression through effects on a number of epigenetic modifications and interaction with transcription factors. The interaction of BAP1–ASXL1 with HCF1–FOXK1 allows deubiquitylation and thereby stabilization of OGT, HCF1, and potentially other unknown targets to regulate transcription. The BAP1–ASXL1–HCF1–OGT complex localizes on numerous gene-regulatory elements, possibly through factors such as FOXK1, and functions as either a gene-specific activator or repressor complex on distinct genes (23–30). BAP1 suppresses tumor development by repressing SLC7A11 expression through regulation of H2A-Ub levels on the SLC7A11 promoter and inducing ferroptosis. SLC7A11 imports extracellular cystine, which is subsequently converted to cysteine in cells; cysteine is a rate-limiting precursor for glutathione (GSH) biosynthesis; GSH is used as a cofactor by glutathione peroxidase 4 to reduce lipid reactive oxygen species (ROS) to lipid alcohols; overproduction of lipid ROS in cells results in ferroptosis (34). By binding BARD1 (2), BAP1 participates in the double-strand DNA break repair process (31, 32). This RAD51-dependent DNA repair pathway is highly regulated and includes many proteins that, in addition to BARD1, may also be substrates for BAP1-mediated ubiquitin hydrolysis. Exposure to DNA-damaging agents, such as asbestos, UV light, and ionizing radiation, induces DNA damage that is rapidly repaired with the help of nuclear BAP1. BAP1 cytoplasmic activities (bottom). The integrity of the IP3R3 ER channels requires the presence of normal amounts of BAP1 that remove ubiquitin from IP3R3. The balance between ubiquitylation mediated by FBXL2 (150) and deubiquitylation mediated by BAP1 (4) maintains a proper amount of IP3R3 required for Ca²⁺ transfer from the ER to the mitochondria. Mitochondria need Ca²⁺ for oxidative phosphorylation; however, higher than physiologic Ca²⁺ concentrations in the mitochondria cause apoptosis, a mechanism used to eliminate cells that accumulate extensive DNA damage that cannot be repaired. This mechanism prevents cells with DNA damage from propagating, thus preventing cancer development (4). MCU, mitochondrial calcium uniporter.