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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  1. 1.

    . et al. Consensus Report of the 2015 Weinman International Conference on Mesothelioma. J. Thorac. Oncol. 11, 1246–1262 (2016)

  2. 2.

    et al. BAP1 and cancer. Nat. Rev. Cancer 13, 153–159 (2013)

  3. 3.

    et al. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene 35, 1996–2002 (2016)

  4. 4.

    et al. Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis 36, 76–81 (2015)

  5. 5.

    et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat. Genet. 43, 1022–1025 (2011)

  6. 6.

    et al. Germline BAP1 mutations predispose also to multiple basal cell carcinomas. Clin. Genet. 88, 273–277 (2015)

  7. 7.

    et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS ONE 7, e35295 (2012)

  8. 8.

    et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat. Genet. 45, 1470–1473 (2013)

  9. 9.

    et al. A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol. Cancer Res. 11, 1061–1071 (2013)

  10. 10.

    et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J. Med. Genet. 48, 856–859 (2011)

  11. 11.

    et al. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. J. Thorac. Oncol. 10, 565–576 (2015)

  12. 12.

    et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330, 1410–1413 (2010)

  13. 13.

    et al. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44, 751–759 (2012)

  14. 14.

    et al. High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. Proc. Natl Acad. Sci. USA 113, 13432–13437 (2016)

  15. 15.

    , , , & Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis. Nat. Commun. 5, 5128 (2014)

  16. 16.

    , , & Deubiquitination of γ-tubulin by BAP1 prevents chromosome instability in breast cancer cells. Cancer Res. 74, 6499–6508 (2014)

  17. 17.

    et al. Germline mutations in BAP1 impair its function in DNA double-strand break repair. Cancer Res. 74, 4282–4294 (2014)

  18. 18.

    et al. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc. Natl Acad. Sci. USA 111, 285–290 (2014)

  19. 19.

    et al. Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol. Cell 54, 392–406 (2014)

  20. 20.

    Calcium signaling. Cell 131, 1047–1058 (2007)

  21. 21.

    The inositol trisphosphate/calcium signaling pathway in health and disease. Physiol. Rev. 96, 1261–1296 (2016)

  22. 22.

    The IP3 receptor/Ca2+ channel and its cellular function. Biochem. Soc. Symp. 74, 9–22 (2007)

  23. 23.

    , , & Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor. Proc. Natl Acad. Sci. USA 101, 17404–17409 (2004)

  24. 24.

    et al. Mitochondrial Ca2+ and apoptosis. Cell Calcium 52, 36–43 (2012)

  25. 25.

    et al. PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330, 1247–1251 (2010)

  26. 26.

    , , , & Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway. Biochem. J. 339, 453–461 (1999)

  27. 27.

    et al. The type III inositol 1,4,5-trisphosphate receptor preferentially transmits apoptotic Ca2+ signals into mitochondria. J. Biol. Chem. 280, 40892–40900 (2005)

  28. 28.

    et al. Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling. Am. J. Pathol. 183, 1654–1666 (2013)

  29. 29.

    , & Cancer associated missense mutations in BAP1 catalytic domain induce amyloidogenic aggregation: a new insight in enzymatic inactivation. Sci. Rep. 5, 18462 (2015)

  30. 30.

    et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat. Genet. 43, 1018–1021 (2011)

  31. 31.

    , , , & Skin punch biopsy explant culture for derivation of primary human fibroblasts. J. Vis. Exp. 77, e3779 (2013)

  32. 32.

    et al. Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity. Proc. Natl Acad. Sci. USA 97, 10214–10219 (2000)

  33. 33.

    et al. Characteristics of nine newly derived mesothelioma cell lines. Ann. Thorac. Surg. 59, 835–844 (1995)

  34. 34.

    et al. Induction of maturation in cultured human monocytic leukemia cells by a phorbol diester. Cancer Res. 42, 1530–1536 (1982)

  35. 35.

    et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 337, 1541–1546 (2012)

  36. 36.

    et al. Subcellular calcium measurements in mammalian cells using jellyfish photoprotein aequorin-based probes. Nat. Protocols 8, 2105–2118 (2013)

  37. 37.

    & Measuring calcium signaling using genetically targetable fluorescent indicators. Nat. Protocols 1, 1057–1065 (2006)

  38. 38.

    , , , & Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nat. Protocols 4, 1582–1590 (2009)

  39. 39.

    & Cryosectioning and immunolabeling. Nat. Protocols 2, 2480–2491 (2007)

  40. 40.

    et al. FBXL2- and PTPL1-mediated degradation of p110-free p85β regulatory subunit controls the PI(3)K signalling cascade. Nat. Cell Biol. 15, 472–480 (2013)

  41. 41.

    et al. Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proc. Natl Acad. Sci. USA 107, 12611–12616 (2010)

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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.

Author information


  1. University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii 96813 USA

    • Angela Bononi
    • , David Larson
    • , Kaitlyn Verbruggen
    • , Mika Tanji
    • , Laura Pellegrini
    • , Valentina Signorato
    • , Federica Olivetto
    • , Sandra Pastorino
    • , Masaki Nasu
    • , Andrea Napolitano
    • , Giovanni Gaudino
    • , Paul Morris
    • , Greg Sakamoto
    • , Haining Yang
    •  & Michele Carbone
  2. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, 44121 Italy

    • Carlotta Giorgi
    • , Simone Patergnani
    • , Valentina Signorato
    • , Federica Olivetto
    • , Alberto Danese
    •  & Paolo Pinton
  3. Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15213 USA

    • Laura K. Ferris
  4. Experimental Imaging Center, San Raffaele Scientific Institute Milano, 20132 Italy

    • Andrea Raimondi
    •  & Carlo Tacchetti
  5. Department of Experimental Medicine, University of Genova, Genova, 16132 Italy

    • Carlo Tacchetti
  6. Cancer Center, New York University, New York, New York 10016, USA

    • Shafi Kuchay
    •  & Harvey I. Pass
  7. Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, Quebec H1T 2M4, Canada

    • El Bachir Affar


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M.C. conceived the study. A.B. led the experiments and prepared the figures. M.C., S.Pas. and H.Y. built pedigrees. M.N. and M.T. genotyped patients and controls. P.M., G.S. and L.K.F. performed skin biopsies. A.B., C.G. and K.V. established fibroblast cell cultures. A.B., C.G., S.Pat. and V.S. independently conducted and reproduced cell death assays. D.L. performed flow cytometry experiments. A.R. and C.T. performed electron microscopy studies. A.B. and C.G. performed subcellular fractionation studies. A.B. performed western blot, co-immunoprecipitation, aequorin-based Ca2+ measurements, and in vitro cell transformation assays. C.G. and S.Pat. performed single-cell Ca2+ measurements. C.G., S.Pat. and F.O. performed immunofluorescence studies. A.D. performed proximity ligation assay studies. A.B., with the help of S.K., performed ubiquitylation assays. L.P. performed qRT–PCR studies. A.B., C.G. and S.Pat., with the help of E.B.A., performed ionizing radiation and ultraviolet radiation studies. A.N., S.Pas., G.G. and H.I.P. discussed the results. M.C., H.Y. and P.P. coordinated the study and oversaw the results. A.B. and M.C. wrote the manuscript with help from co-authors.

Competing interests

M.C. has pending patent applications on BAP1. M.C. provides consultation for mesothelioma diagnosis. The authors have no other potential competing financial interests.

Corresponding authors

Correspondence to Haining Yang or Paolo Pinton or Michele Carbone.

Reviewer Information Nature thanks M. Campanella, N. Hayward, K. D. Wilkinson and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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  1. 1.

    Supplementary Figures

    This file contains Supplementary Figure 1 (Pedigrees of W and L family members), Supplementary Figure 2 (Uncropped scans with size marker indications) and Supplementary Figure 3 (Uncropped EM images).

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    Supplementary Tables

    This file contains Supplementary Tables 1 and 2.

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