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E.B. Affar



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    MS 08 - BAP1 Cancer Syndrome and Mesothelioma (ID 26)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MS08.02 - BAP1 and Ubiquitination (ID 1878)

      14:40 - 15:00  |  Author(s): E.B. Affar

      • Abstract
      • Presentation

      Abstract:
      The deubiquitinase (DUB) BAP1 recently emerged as a major tumor suppressor inactivated in several malignancies notably mesothelioma. With the aim of defining the BAP1 mechanism of action, we previously conducted a tandem affinity immunopurification of BAP1-associated proteins and found that most of the interacting partners are transcription factors and cofactors. Notably, BAP1 forms a complex with the Host Cell Factor (HCF-1), the O-linked N-acetyl-Glucosamine Transferase (OGT), the Lysine Specific Demethylase KDM1B, the Additional Sex Comb Like proteins ASXL1 and ASXL2 (ASXL1/2), the Forkhead Box transcription factors FOXK1 and FOXK2 as well as the zinc finger transcription factor Yin Yang 1 (YY1). We found that BAP1 regulates the expression of genes involved in cell proliferation and is recruited to gene regulatory regions to activate transcription. BAP1 is also recruited to the site of DNA double strand breaks to promote repair by homologous recombination. Moreover, this DUB appears to be also finely regulated by post-translational modifications including phosphorylation and ubiquitination. Interestingly, the ortholog of BAP1 in drosophila, named Calypso, deubiquitinates histone H2A on lysine 119 (H2Aub). H2Aub is a critical epigenomic modification involved in transcriptional and DNA repair, and is associated with stem cell function, development, cell proliferation and cancer. Calypso associates with Additional Sex Comb (ASX) and forms the Polycomb Repressive DUB (PR-DUB) complex. Recently, we provided insights into the importance of BAP1-interacting partners, ASXL1 and ASXL2 (two orthologs of ASX) in promoting H2A deubiquitination. We found that BAP1 forms two mutually exclusive complexes with ASXL1 and ASXL2. ASXL1 and ASXL2 use their highly conserved ASXM domain to interact with the C-terminal domain (CTD) of BAP1, and these factors regulate each other’s protein stability. Significantly, through mutational analysis, we found that ASXM enhances BAP1 binding to ubiquitin and stimulates its DUB activity. Importantly, these functions require intramolecular interactions in BAP1 that generate a Composite Ubiquitin Binding Interface (CUBI). Gain and loss of function studies indicated that BAP1, ASXL1 and ASXL2 play critical roles in the coordination of cell cycle progression. Notably, overexpression of BAP1 or ASXL2 trigger the p53/p21 DNA damage response and cellular senescence, and these effects are abolished by mutations of the CTD or ASXM interaction domains. Furthermore, we showed that cancer-associated inactivation of BAP1/ASXL1/2 DUB activity disrupts coordination of cell proliferation. Altogether, our results indicate that the mammalian BAP1 is an authentic DUB for H2A that regulates chromatin function and exerts a tight control on cell cycle progression. Moreover, our studies provide a mechanistic link between H2A deubiquitination, BAP1 interacting partners and tumor suppression.

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