BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis1,2,3. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1+/−) developed one and often several BAP1−/− malignancies in their lifetime4, mostly malignant mesothelioma, uveal melanoma2,5, and so on6,7,8,9,10. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers8,11,12,13,14. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity15,16,17. The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination18, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca2+) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1+/− carriers cause reduction both of IP3R3 levels and of Ca2+ flux, preventing BAP1+/− cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive 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 activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene–environment interaction in human carcinogenesis.
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We are grateful to the members of the L and W families who donated their cells to our research. We acknowledge K. Dixon for advice on ultraviolet radiation studies, M. Pagano for advice on ubiquitylation assays, H. Yu for advice on DNA repair studies, I. Pagano for review of all statistical analyses, and G. Khan for technical support. This work was supported by grants National Cancer Institute (NCI) R01 CA198138 to M.C.; by NCI R01 CA160715, DOD CA120355 to H.Y.; by the University of Hawai’i Foundation, which received unrestricted donations to support mesothelioma research from Honeywell International, to M.C.; by The Riviera United 4-a Cure to M.C. and H.Y.; and by the Italian Association for Cancer Research (AIRC) (IG-18624, MFAG13521) and the Italian Ministry of Health to P.P. and C.G. P.P. thanks C. degli Scrovegni for support.
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STAT3 localizes to the ER, acting as a gatekeeper for ER-mitochondrion Ca2+ fluxes and apoptotic responses
Cell Death & Differentiation (2019)