Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1 (PubMed:12485996, PubMed:18757409, PubMed:20436459, PubMed:25451922, PubMed:35051358). Catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-120' (H2AK119ub1) (PubMed:20436459, PubMed:25451922, PubMed:30664650, PubMed:35051358). Does not deubiquitinate monoubiquitinated histone H2B (PubMed:20436459, PubMed:30664650).
The PR-DUB complex is an epigenetic regulator of gene expression and acts as a transcriptional coactivator, affecting genes involved in development, cell communication, signaling, cell proliferation and cell viability (PubMed:20805357, PubMed:30664650, PubMed:36180891). Antagonizes PRC1 mediated H2AK119ub1 monoubiquitination (PubMed:30664650). As part of the PR-DUB complex, associates with chromatin enriched in histone marks H3K4me1, H3K4me3, and H3K27Ac, but not in H3K27me3 (PubMed:36180891).
Recruited to specific gene-regulatory regions by YY1 (PubMed:20805357). Acts as a regulator of cell growth by mediating deubiquitination of HCFC1 N-terminal and C-terminal chains, with some specificity toward 'Lys-48'-linked polyubiquitin chains compared to 'Lys-63'-linked polyubiquitin chains (PubMed:19188440, PubMed:19815555). Deubiquitination of HCFC1 does not lead to increase stability of HCFC1 (PubMed:19188440, PubMed:19815555).
Interferes with the BRCA1 and BARD1 heterodimer activity by inhibiting their ability to mediate ubiquitination and autoubiquitination (PubMed:19117993). It however does not mediate deubiquitination of BRCA1 and BARD1 (PubMed:19117993). Able to mediate autodeubiquitination via intramolecular interactions to counteract monoubiquitination at the nuclear localization signal (NLS), thereby protecting it from cytoplasmic sequestration (PubMed:24703950).
Negatively regulates epithelial-mesenchymal transition (EMT) of trophoblast stem cells during placental development by regulating genes involved in epithelial cell integrity, cell adhesion and cytoskeletal organization (PubMed:34170818)
Core component of the polycomb repressive deubiquitinase (PR-DUB) complex, at least composed of BAP1, one of ASXL1, ASXL2 or (probably) ASXL3, and one of MBD5 or MBD6 (PubMed:20436459, PubMed:24634419, PubMed:30664650, PubMed:36180891). The PR-DUB core associates with a number of accessory proteins, including FOXK1, FOXK2, KDM1B, HCFC1, YY1 and OGT; KDM1B specifically associates with ASXL2 PR-DUB complexes (Probable) (PubMed:20805357, PubMed:30664650). The BAP1 deubiquitinase activity is not required for PR-DUB assembly (PubMed:20805357).
Homodimerizes (via coiled-coil hinge-region between the UCH and ULD domains) to mediate assembly of 2 copies of the BAP1-ASXL heterodimer into a bisymmetric tetramer; dimerization enhances association with nucleosomes (PubMed:30258054, PubMed:35446349). The PR-DUB complex associates with nucleosomes to mediate deubiquitination of 'lys-120' of histone H2AK118ub1 substrates; the association requires the positively charged C-terminal tail of BAP1 (PubMed:30258054, PubMed:36991118, PubMed:37556531). Interacts (via ULD domain) with ASXL1 (via DEUBAD domain); the interaction is direct and forms a ubiquitin binding cleft (PubMed:36180891, PubMed:36991118, PubMed:37556531).
The interaction with ASXL1 stabilizes BAP1 but is not required for nucleosome binding (PubMed:36180891). Associates (via C-terminus) with nucleosome and chromatosome complexes through direct interaction with DNA and the histone3/4 dimer; this association displaces the histone-2A C-terminal tail, extending and orienting the H2AK118ub1 substrate towards the BAP1 deubiquitinase active site (PubMed:36991118, PubMed:37556531). Also interacts (via arginine finger) directly with the histone H2A-H2B acidic patch; this interaction is not critical for nucleosome-chromatosome association but may play a role in orienting the H2AK118ub1 substrate towards the PR-DUB complex active site (PubMed:36991118).
Interacts with BRCA1 (via the RING finger) (PubMed:19117993, PubMed:9528852). Interacts (via HBM-like motif) with HCFC1 (PubMed:19188440, PubMed:19815555, PubMed:20805357). Interacts (via a C-terminal region overlapping the ULD domain) with YY1; the interaction is direct and requires the interaction with HCFC1 (PubMed:20805357).
Interacts (when phosphorylated at Thr-493) with FOXK1 (PubMed:25451922). Interacts (when phosphorylated at Thr-493) with FOXK2; leading to recruitment of the PR-DUB complex and repression of FOXK2 target genes (PubMed:24748658, PubMed:25451922). Interacts (via non-classical PY-NLS) with TNPO1/transportin-1 (via HEAT repeats 8-12); the interaction is direct, mediates BAP1 nuclear localization and disrupts BAP1 homodimerization (PubMed:35446349).
Interacts (via C-terminus) with KPNA1/importin alpha5 and KPNA2/importin alpha1; these interactions can contribute to BAP1 nuclear localization but are less important than the interaction with TNPO1/transportin-1 (PubMed:35446349). The interaction with TNPO1/transportin-1 disrupts homodimerization and blocks ubiquitination by UBE2O (PubMed:35446349)
Highly expressed in testis, placenta and ovary (PubMed:9528852). Expressed in breast (PubMed:9528852). levels in the placenta increase over the course of pregnancy (PubMed:34170818)
Possesses 2 overlapping nuclear localization sequences (NLS), a classic bipartite NLS and a non-classical PY-NLS (PubMed:35446349). The classical NLS probably mediates import via the importin alpha/beta system while the PY-NLS mediates nuclear import via the transportin system (PubMed:35446349)
The positively charged C-terminal tail stabilizes the interaction with nucleosomes/chromatosomes through interaction with the DNA backbone (PubMed:30258054, PubMed:36991118). Binding of ASXL1 just upstream of the positively charged C-terminal tail may stabilize its orientation to align the PR-DUB with its H2AK118ub1 substrate (PubMed:36991118)
The ubiquitin C-terminal hydrolase (UCH) domain, together with the DEUBAD domain of ASXL1, forms the ubiquitin binding cleft of the PR-DUB complex
The positively charged Arg-finger motif mediates interaction with the histone H2A-H2B acidic patch; this interaction is critical for nucleosomal H2AK119ub1 deubiquitination activity but not nucleosomal binding
An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.
An autosomal dominant condition characterized by predisposition to develop a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, lung adenocarcinoma and meningioma.
Most common intraocular malignancy, arising from melanocytes in the iris, ciliary body, or choroid. Metastases develop in more than 30% of case patients, almost invariably in the liver, with poor prognosis.
An autosomal dominant neurodevelopmental disorder characterized mainly by mild global developmental delay apparent from infancy or early childhood, and behavioral problems, including autism in most patients. Intellectual development may be mildly delayed, borderline, or even normal. Additional variable systemic features may include poor overall growth, hypotonia, distal skeletal anomalies, seizures, and non-specific dysmorphic facial features.
Click a pathway to open the interactive Reactome viewer.
Genes with an experimentally identified or computationally predicted synthetic-lethal relationship to UBAP1, aggregated across our SSL data sources. Click any partner node to view that gene’s page.
Nodes and edges are coloured by the SSL data source. Partners appearing in more than one source are shown in grey.
Total Trials Found: 2
| NCT ID | Condition | Brief Title | Phase | Status |
|---|---|---|---|---|
| NCT05885529 | Traumatic Brain Injury | Glial Fibrillary Acidic Protein (GFAP) and Ubiquitin Carboxy-terminal Hydrolase L1 (UCH-L1) to Exclude Lesions Linked to Significant Traumatic Brain Injuries | N/A | RECRUITING |
| NCT06449183 | Mild Traumatic Brain Injury | VIDAS® TBI Real Life Performance in Subjects With Mild Traumatic Brain Injury (mTBI) | NA | COMPLETED |
| NCT05941637 | Clear Cell Kidney Cancer, Kidney Cancer, Kidney Cancer With PBRM1/BAP1/VHL/SETD2 Mutations | An Expanded Access Program to Axitinib is Available for Patients With Advanced Forms of Kidney Cancer (Ductal; Papillary; Chromophobic; Oncocytic) With Mutations in VHL, PBRM1 / BAP1, SETD2, VEGF) | N/A | NO_LONGER_AVAILABLE |
| NCT04431024 | Familial Cancer, BRCA1-Associated Protein-1 (BAP1) Mutations, Tumor Predisposition Syndrome (TPDS), Mesothelioma | Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Surgical Surveillance for Early Detection of Mesotheliomas in Patients With BAP1 Tumor Predisposition Syndrome | N/A | RECRUITING |
| NCT06581757 | Subarachnoid Haemorrhage (SAH) | Serum GFAP and UCHL1: Evaluation of Their Predictive Value for SAH | N/A | TERMINATED |
| NCT03830229 | Mesothelioma, Families | Long Term Follow-up of Mesothelioma Patients and Their Family Members With Germline Mutations in BAP1 and Other Genes | N/A | RECRUITING |
| NCT05960773 | Mesothelioma, Malignant Mesothelioma (MM), Early-stage Mesothelioma, Subclinical Mesothelioma, BRCA1-Associated Protein-1 (BAP1) Mutations, Early-stage BAP1-associated Malignancies | Decitabine/Cedazuridine (INQOVI), an Oral DNA Demethylating Agent, in Subjects With BAP1 Cancer Predisposition Syndrome and Subclinical, Early-Stage Mesothelioma | PHASE2 | SUSPENDED |
| NCT03786796 | Renal Cell Carcinoma, Metastatic Renal Cell Carcinoma, Kidney Cancer, Renal Carcinoma, Kidney Cancer Metastatic | Study of Olaparib in Metastatic Renal Cell Carcinoma Patients With DNA Repair Gene Mutations | PHASE2 | RECRUITING |
| NCT03050268 | Acute Leukemia, Adenomatous Polyposis, Adrenocortical Carcinoma, AML, BAP1 Tumor Predisposition Syndrome, Carney Complex, Choroid Plexus Carcinoma, Constitutional Mismatch Repair Deficiency Syndrome, Diamond-Blackfan Anemia, DICER1 Syndrome, Dyskeratosis Congenita, Emberger Syndrome, Familial Acute Myeloid Leukemia, Familial Adenomatous Polyposis, Fanconi Anemia, Familial Cancer, Familial Wilms Tumor, Familial Neuroblastoma, GIST, Hereditary Breast and Ovarian Cancer, Hereditary Paraganglioma-Pheochromocytoma Syndrome, Hodgkin Lymphoma, Juvenile Polyposis, Li-Fraumeni Syndrome, Lynch Syndrome, MDS, Melanoma Syndrome, Multiple Endocrine Neoplasia Type 1, Multiple Endocrine Neoplasia Type 2, Neuroblastoma, Neurofibromatosis Type 1, Neurofibromatosis Type II, Nevoid Basal Cell Carcinoma Syndrome, Non Hodgkin Lymphoma, Noonan Syndrome and Other Rasopathy, Overgrowth Syndromes, Pancreatic Cancer, Peutz-Jeghers Syndrome, Pheochromocytoma/Paraganglioma, PTEN Hamartoma Tumor Syndrome, Retinoblastoma, Rhabdoid Tumor Predisposition Syndrome, Rhabdomyosarcoma, Rothmund-Thomson Syndrome, Tuberous Sclerosis, Von Hippel-Lindau Disease | Familial Investigations of Childhood Cancer Predisposition | N/A | RECRUITING |
| NCT04792463 | Uveal Melanoma, Cutaneous Melanoma, BAP1 Gene Mutation, Renal Cell Carcinoma, Mesothelioma, Hepatocellular Carcinoma, Cholangiocarcinoma, Meningioma Atypical | Frequency and Clinical Phenotype of BAP1 Hereditary Predisposition Syndrome | N/A | RECRUITING |