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Identification of BRCA1-associated protein 1 (BAP1)-associated proteins

ABSTRACT: BRCA1-associated protein 1 (BAP1) is a multidomain deubiquitinase (DUB) with a ubiquitin carboxyl-terminal hydrolase (UCH) domain at its N-terminus. BAP1 mainly localizes in the nucleus and primarily functions as a transcriptional regulator in diverse cellular pathways, including cell proliferation, cell cycle progression, cell death and DNA repair. However, a comprehensive understanding of the mechanism by which the nucleocytoplasmic trafficking of BAP1 is regulated remains lacking. To identify protein factors that may be responsible for the nuclear import of BAP1, we used transiently expressed a N-terminally FLAG-tagged BAP1 in HEK293 freestyle (HEK293F) cells as a bait to pull down BAP1-interacting proteins for mass spectrometry-based proteomic analysis.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture

SUBMITTER: Tzu-Jing Yang

LAB HEAD: Shang-Te Danny Hsu

PROVIDER: PXD030044 | Pride | 2022-04-14

REPOSITORIES: Pride

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			Action	DRS
	2021-0702_Flag-HA-BAP1.raw	Raw
	2021-0702_Flag-HA-BAP1_F068486.csv	Csv
	F068486.dat	Other

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Proteomic analysis identifies novel BRCA1-associated protein 1 binding proteins

Project description:BRCA1-associated protein 1 (BAP1) is a tumor suppressor and its loss can result in mesothelioma, uveal and cutaneous melanoma, clear cell renal cell carcinoma and bladder cancer. BAP1 is a deubiquitinating enzyme of the UCH class that has been implicated in various cellular processes like cell growth, cell cycle progression, ferroptosis and ER metabolic stress response. Here, we identify novel BAP1 interacting proteins in the cytoplasm by expressing GFP-tagged BAP1 in an endogenous BAP1 deficient cell line using affinity purification followed by mass spec (AP-MS) analysis. Among these novel interacting proteins are all subunits of the heptameric coat protein complex I (COPI) that is involved in vesicle formation and protein cargo binding and sorting.

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MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer

Project description:The BRCA1-associated protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase (UCH), which forms a multi-protein complex with different epigenetic factors such as ASXL1-3, and FOXK1/2. At chromatin, BAP1 catalyzes the removal of mono-ubiquitination on histone H2AK119 in collaboration with other subunits within the complex, and therefore functions as a transcriptional activator. However, the crosstalk between different subunits and how these subunits impact BAP1 function remains unclear. Here, we report the identification of the methyl-CpG-binding domain proteins 5 and 6 (MBD5 and MBD6) that bind to the C-terminal PHD fingers of the large scaffold subunits ASXL1-3 and stabilize the BAP1 complex at chromatin. We further identified a previously uncharacterized Drosophila protein, the six-banded (SBA), as the ortholog of human MBD5/6. We demonstrated the core module of the BAP1 complex is structurally and functionally conserved during the evolution from Drosophila (Calypso/ASX/SBA) to human cells (BAP1/ASXL/MBD). Dysfunction of the BAP1 complex induced by the misregulation/mutations in each subunit is frequent in human cancer. In BAP1-dependent human cancers, MBD6 tends to be a dominant form. Depletion of MBD6 leads to a global loss of BAP1 occupancy at chromatin, resulting in a reduction of BAP1-dependent gene expression and tumor growth in vitro and in vivo. In summary, our study has uncovered MBD5/6 as important regulators of the BAP1 complex and transcription, and sheds light on the therapeutic potential of targeting MBD5/6 in human cancer.

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Project description:BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, via deubiquitination of histone H2AK119ub and other substrates. BAP1 is an important tumour suppressor in human, expressed and functional across many cell-types and tissues, including those of the immune system. B lymphocytes are the mediators of humoral immune response, however the role of BAP1 in B cell development and physiology remains poorly understood. Here we characterize a mouse line with a selective deletion of BAP1 within the B cell lineage (Bap1fl/fl mb1-Cre) and establish a cell intrinsic role of BAP1 in the regulation of B cell development. We demonstrate a depletion of large pre-B cells, transitional B cells, and mature B cells in Bap1fl/fl mb1-Cre mice. We characterize broad transcriptional changes in BAP1-deficient pre-B cells, map BAP1 binding across the genome, and analyze the effects of BAP1-loss on histone H2AK119ub levels and distribution. Overall, our work establishes a cell intrinsic role of BAP1 in B lymphocyte development, and suggests its contribution to the regulation of the transcriptional programs of cell cycle progression, via the deubiquitination of histone H2AK119ub.

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Regulation of B lymphocyte development by histone H2A deubiquitinase BAP1 (BAP1_ChIP-Seq)

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2019-01-28 | PXD011808 | Pride

Pervasive Roles of Ubiquitination in Orchestrating the Deubiquitinase Activity and Function of the BAP1/ASXL2 Tumor Suppressor Complex

Project description:The tumor suppressor and deubiquitinase (DUB) BAP1 regulates chromatin-associated processes and is frequently mutated in various malignancies. BAP1 and its drosophila orthologue Calypso assemble DUB complexes with ASXL-1, -2, -3 paralogues and ASX respectively, and these cofactors are required for stimulating their DUB activity. However how the DUB activity of BAP1 is regulated remains largely unknown. Here we show that BAP1 promotes monoubiquitination of ASXLs on the ASXM/DEUBAD domain. ASXL2 monoubiquitination promotes its stability or proteasomal degradation, stimulates BAP1 DUB activity and is required for mammalian cell proliferation. Monoubiquitination of ASXL2 is directly catalyzed by UBE2E family of ubiquitin conjugating enzymes and is regulated by deubiquitination. Monoubiquitination of ASX is regulated by Calypso and is required for drosophila development. We further revealed a switch mechanism that tightly regulate BAP1 function, as a monoubiquitination of BAP1 UCH domain is mutually exclusive with ASXL2 monoubiquitination, thus ensuring highly coordinated DUB-mediated signaling.

2018-09-28 | PXD011124 | Pride

Rare germline heterozygous missense variants of the BRCA1-Associated Protein 1 gene, BAP1, heterozygous missense variants cause a syndromic neurodevelopmental disorder

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