BAP1 regulates IP3R3-mediated Ca ²⁺ flux to mitochondria suppressing cell transformation

Abstract

BRCA1-associated protein 1 (BAP1) is a potent tumor suppressor gene that modulates environmental carcinogenesis ^{1- 3} . All carriers of inherited heterozygous germline BAP1 inactivating mutations ( BAP1 ^+/-) developed one and often several BAP1 ^-/- malignancies in their lifetime ⁴ , mostly malignant mesothelioma (MM), uveal melanoma (UVM) ^{2, 5} , etc ^{6- 10} . Moreover, BAP1 acquired biallelic mutations are frequent in human cancers ^{8, 11- 14} . BAP1 tumor suppressor activity has been attributed to its nuclear localization where BAP1 helps maintaining genome integrity ^{15- 17} . The possible activity of BAP1 in the cytoplasm was unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination ¹⁸ , indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. We discovered that BAP1 localizes at the endoplasmic reticulum (ER). Here BAP1 binds, deubiquitylates and stabilizes type-3 inositol-1,4,5-trisphosphate-receptor (IP3R3), modulating calcium (Ca ²⁺) release from the ER into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1 ^+/- carriers caused reduction of both IP3R3 levels and Ca ²⁺ flux, preventing BAP1 ^+/- cells that had accumulated DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survived genotoxic stress resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1 ^+/- carriers results from the combined reduced nuclear and cytoplasmic BAP1 activities. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction.