Fig. 1

BAP-1 modulates DNA repair and Ca⁺⁺ levels. Increased DNA damage is observed in BAP-1 mutant cells (BAP-1^{+/−, −/−}) after exposure to asbestos, ultraviolet light, radiation, and chemotherapy as well as in cells with reduced BAP1 levels by siRNA experiments. In the nucleus, BAP-1 regulates DNA repair. In the cytoplasm, BAP-1 stabilizes by deubiquitylation (Ub) the IP3R3 receptor channel that in turn regulates Ca⁺⁺ transfer from the endoplasmic reticulum (ER), in which Ca⁺⁺ is normally stored, to the cytoplasm. Calcium ions, released from the ER, flow through the voltage-dependent anion channel (VDAC) located on the outer mitochondrial membrane, and then are actively transported inside the mitochondria by the mitochondrial uniporter channel complex (MCU) located on the inner mitochondrial membrane. Here, Ca⁺⁺ is required for the normal activity of the Krebs’ cycle. In BAP-1^{+/−, −/−} cells, reduced Ca⁺⁺ concentrations impair mitochondrial respiration (Krebs cycle), and the cells switch to aerobic glycolysis (Warburg effect). Moreover, in normal cells (BAP-1^+/+), following a DNA damage that cannot be repaired, higher amounts of calcium ions are released from the ER and the consequently higher mitochondrial Ca⁺⁺ concentration, causes the release of cytochrome c from mitochondria into the cytosol, thus starting the apoptotic cascade. In contrast, BAP-1 mutated cells, in which an insufficient amount of Ca⁺⁺ is released, cannot start the apoptosis process, therefore the mutated cells are able to divide and may give rise to malignancy. Cartoon adapted from Carbone et al. [5]