{"gene":"BAP1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2018,"finding":"BAP1 represses SLC7A11 (cystine transporter) expression by reducing histone H2A ubiquitination (H2Aub) on the SLC7A11 promoter in a deubiquitinating-dependent manner, thereby inhibiting cystine uptake, elevating lipid peroxidation, and promoting ferroptosis as a tumor suppressor mechanism.","method":"Integrated transcriptomic/epigenomic analyses, ChIP assays, functional deubiquitinase-dead mutants, cystine uptake assays, lipid peroxidation measurements, and in vivo tumor models","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, mutagenesis, in vitro and in vivo assays) in a single rigorous study with functional validation","pmids":["30202049"],"is_preprint":false},{"year":2017,"finding":"BAP1 localizes at the endoplasmic reticulum where it binds, deubiquitylates, and stabilizes the type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), thereby modulating calcium (Ca2+) release from the ER into the cytosol and mitochondria to promote apoptosis.","method":"Subcellular fractionation, co-immunoprecipitation, deubiquitylation assays, Ca2+ flux measurements, cellular transformation assays, and genetic models (BAP1+/- cells)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP, biochemical deubiquitylation assay, Ca2+ flux measurement, and transformation readout across multiple orthogonal methods","pmids":["28614305"],"is_preprint":false},{"year":2013,"finding":"BAP1 is required for efficient assembly of homologous recombination (HR) factors BRCA1 and RAD51 at ionizing radiation-induced foci; BAP1-deficient cells are sensitive to DSB-inducing agents, defective in HR-mediated gene conversion, and exhibit increased chromosomal breaks. Both catalytic activity and IR-induced phosphorylation of BAP1 are required for its recruitment to DSB sites and for DNA repair.","method":"RNAi screen, gene knockout in DT40 cells, IR sensitivity assays, immunofluorescence for BRCA1/RAD51 foci, I-SceI-induced DSB assay, phosphomutant analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal phenotypic readouts, site-specific DSB recruitment, and phosphomutant mechanistic follow-up","pmids":["24347639"],"is_preprint":false},{"year":2009,"finding":"BAP1 interacts with host cell factor-1 (HCF-1) via an HCF-1 binding motif (HBM); HCF-1N is modified with Lys-48-linked polyubiquitin chains on its Kelch domain, and BAP1 deubiquitinates HCF-1N. This interaction is required for BAP1-mediated cell growth regulation.","method":"Mass spectrometry co-purification, co-immunoprecipitation, ubiquitin chain-linkage analysis, RNAi depletion, dominant-negative mutant overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-identified interaction confirmed by Co-IP, biochemical deubiquitination, and HBM-mutant functional rescue experiments","pmids":["19815555"],"is_preprint":false},{"year":2015,"finding":"BAP1 loss in mice results in increased H3K27me3 levels, elevated EZH2 expression, and enhanced PRC2-target repression; this is mechanistically linked to a marked decrease in H4K20 monomethylation (H4K20me1), and SETD8 (the H4K20me1 methyltransferase) overexpression reduces EZH2 expression and abrogates BAP1-mutant cell proliferation.","method":"Conditional Bap1 knockout mice, ChIP-seq for histone marks, epistasis via Bap1/Ezh2 double conditional deletion, SETD8 overexpression rescue experiments","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis (double KO), ChIP-seq histone mark analysis, and rescue experiments across multiple orthogonal approaches","pmids":["26437366"],"is_preprint":false},{"year":2016,"finding":"BAP1's C-terminal extension auto-recruits BAP1 to nucleosomes (in an acidic patch-independent manner), forming an unproductive initial complex that is activated by the DEUBAD domains of ASXL1, ASXL2, or ASXL3 to increase BAP1's affinity for ubiquitin on H2A and drive deubiquitination. The reaction is specific for Polycomb H2AK119 modifications and cannot deubiquitinate DNA damage-dependent H2A K13/K15 ubiquitination.","method":"Biochemical reconstitution with purified nucleosomes, mutagenesis of BAP1 C-terminal extension, DEUBAD domain binding assays, specificity assays comparing H2AK119 vs H2AK13/15 substrates","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis and substrate specificity assays demonstrating catalytic mechanism","pmids":["26739236"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of human BAP1 and the ASXL1 DEUBAD domain in complex with a H2AK119Ub nucleosome reveals the molecular interactions of BAP1 and ASXL1 with histones and DNA that restructure the nucleosome to establish specificity for H2AK119Ub; >50 cancer-associated mutations in BAP1 and ASXL1 are structurally explained as dysregulating this reaction.","method":"Cryo-EM structure determination, biochemical deubiquitination assays, mutagenesis of contact residues, cellular validation","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with biochemical and cellular validation, mutagenesis of structure-guided residues","pmids":["37556531"],"is_preprint":false},{"year":2019,"finding":"BAP1-associated core complex (BAP1.com), containing ASXL1/2/3, functions as a transcriptional activator to safeguard transcriptionally active genes against silencing by Polycomb Repressive Complex 1 (PRC1), rather than participating in Polycomb-mediated silencing as previously proposed.","method":"CRISPR/Cas9-generated isogenic cell lines, integrative ChIP-seq/RNA-seq, catalytic mutant BAP1 complementation, H2AK119Ub profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic CRISPR lines, multiple orthogonal genomic/epigenomic methods, catalytic mutant controls","pmids":["30664650"],"is_preprint":false},{"year":2015,"finding":"BAP1 acts as a deubiquitinase for KLF5; BAP1 directly interacts with KLF5 and stabilizes it via deubiquitination. KLF5 is a component of the BAP1/HCF-1 complex, which promotes cell cycle progression partly by inhibiting p27 gene expression. BAP1 knockdown inhibits tumorigenicity and lung metastasis, partially rescued by ectopic KLF5 expression.","method":"Genome-wide siRNA DUB screen, co-immunoprecipitation, in vitro deubiquitination assay, ubiquitination assay, rescue experiments, xenograft tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen hit validated with Co-IP, biochemical deubiquitination, and in vivo rescue across multiple orthogonal methods","pmids":["26419610"],"is_preprint":false},{"year":2018,"finding":"BAP1 forms a trimeric protein complex with HMGB1 and histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and secretion; reduced BAP1 levels cause increased ubiquitylation and degradation of HDAC1, leading to increased HMGB1 acetylation and its active secretion, promoting mesothelial cell transformation.","method":"Co-immunoprecipitation, ubiquitylation assays, serum HMGB1 acetylation measurements (ELISA), cellular transformation assays in BAP1+/- cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP of trimeric complex, biochemical ubiquitylation/acetylation assays, and in vivo transformation readout with mechanistic chain established","pmids":["34815344"],"is_preprint":false},{"year":2018,"finding":"BAP1 is a component of the DRED repressor complex in erythroid cells; it maintains NCoR1 occupancy at the β-globin locus, and BAP1 inhibition massively induces γ-globin synthesis, demonstrating a role in γ-globin gene repression.","method":"Co-immunoprecipitation, ChIP assays at β-globin locus, BAP1 inhibition in erythroid cells with γ-globin expression readout","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP establishing complex occupancy, functional readout by BAP1 inhibition, single lab","pmids":["30463901"],"is_preprint":false},{"year":2019,"finding":"BAP1 promotes restart of hydroxyurea-induced stalled replication forks by recruiting the INO80 chromatin remodeler to stalled forks; BAP1 depletion abrogates INO80 binding at replication forks, increases RAD51 foci, and causes hypersensitivity to HU, rescued by INO80 re-expression.","method":"DNA fiber assays (fork restart), ChIP at replication forks, immunofluorescence, HU sensitivity assays, ectopic INO80 rescue","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fork restart assay, chromatin binding evidence, and genetic rescue, single lab","pmids":["31657441"],"is_preprint":false},{"year":2021,"finding":"CHIP (E3 ubiquitin ligase) polyubiquitinates INO80 in an Hsp70-dependent manner; BAP1 and CHIP act in concert to stabilize INO80 and promote its chromatin binding, which is required for efficient replication fork progression.","method":"Co-immunoprecipitation, ubiquitination assays, half-life (cycloheximide chase) experiments, DNA fiber assays, ChIP","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitination assays and functional fork progression, single lab","pmids":["33658435"],"is_preprint":false},{"year":2018,"finding":"BAP1 induces cell death via interaction with 14-3-3 protein; the BAP1-14-3-3 association releases the apoptotic inducer Bax from 14-3-3, promoting cell death through the intrinsic apoptosis pathway.","method":"Co-immunoprecipitation, Bax release assay, apoptosis assays, cell cycle analysis, xenograft tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating protein interaction and mechanistic Bax release assay, single lab","pmids":["29686263"],"is_preprint":false},{"year":2015,"finding":"BAP1 binds to MCRS1 (a centrosome/spindle assembly component) and stabilizes it via deubiquitination, contributing to chromosome stability in renal cell carcinoma.","method":"Co-immunoprecipitation, deubiquitination assay, chromosome stability assays, expression correlation in ccRCC tissues","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in vitro deubiquitination assay with functional chromosome stability readout, single lab","pmids":["26300492"],"is_preprint":false},{"year":2020,"finding":"BAP1 physically binds and deubiquitinates PTEN, inhibiting ubiquitination-mediated PTEN degradation and thereby stabilizing PTEN protein; this suppresses the AKT signaling pathway and prostate cancer progression, which is reversed by BAP1 knockdown and rescued by PTEN re-expression.","method":"Co-immunoprecipitation, deubiquitination assay, knockdown/overexpression in PCa cells, AKT signaling measurements, PTEN re-expression rescue, xenograft models","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and deubiquitination assay with epistatic rescue, single lab","pmids":["33155366"],"is_preprint":false},{"year":2020,"finding":"BAP1 stabilizes the LATS tumor suppressor kinase (Hippo pathway) by preventing its ubiquitin-dependent proteasomal degradation; BAP1-deficient pancreatic tumors show enhanced LATS degradation and Hippo pathway deregulation.","method":"Conditional Bap1 KO mouse model (KrasG12D background), ubiquitination/proteasome assays for LATS, histological and pathway analysis of pancreatic tumors","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with biochemical ubiquitination evidence for LATS stabilization, single lab","pmids":["31988076"],"is_preprint":false},{"year":2021,"finding":"BAP1 binds, deubiquitylates, and stabilizes HIF-1α during hypoxia; BAP1 interacts with the N-terminal region of HIF-1α where HIF-1α binds DNA and dimerizes with HIF-1β. BAP1 residues I675, F678, I679, and L691 in the C-terminal domain-NLS are required for HIF-1α interaction. Loss of BAP1 reduces nuclear HIF-1α levels in hypoxic cells.","method":"Co-immunoprecipitation, deubiquitylation assays, site-directed mutagenesis of BAP1 C-terminal residues, computational docking, immunofluorescence/IHC in BAP1-null cells and mesothelioma biopsies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis, biochemical deubiquitylation, and cellular/tissue validation, single lab","pmids":["36656861"],"is_preprint":false},{"year":2022,"finding":"Transportin-1 (TNPO1/Karyopherin β2) is the primary nuclear transporter of BAP1, targeting an atypical C-terminal proline-tyrosine nuclear localization signal (PY-NLS). TNPO1 binding dissociates dimeric BAP1 and sequesters monoubiquitination sites flanking the PY-NLS, counteracting UBE2O-mediated cytosolic retention of BAP1.","method":"Co-immunoprecipitation, nuclear import assays, PY-NLS mutagenesis, BAP1 dimerization analysis, UBE2O competition assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with NLS mutagenesis and functional nuclear import assay, single lab","pmids":["35446349"],"is_preprint":false},{"year":2018,"finding":"Mutant ASXL1 (C-terminally truncated) undergoes increased monoubiquitination, which in turn increases the catalytic function of BAP1; the hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation and leukaemogenesis by removing H2AK119 ubiquitination at posterior HOXA genes and IRF8 loci.","method":"Biochemical ubiquitination assays, deubiquitinase activity assays of BAP1/ASXL1-MT complex, ChIP for H2AK119ub, haematopoietic progenitor differentiation assays, BAP1 depletion in ASXL1-MT leukemia cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical activity assays and ChIP with genetic depletion, single lab","pmids":["30013160"],"is_preprint":false},{"year":2021,"finding":"BAP1 downregulation is essential to trigger epithelial-mesenchymal transition (EMT) during trophoblast differentiation; BAP1's function in suppressing EMT is dependent on its binding to ASXL1/2 proteins to form the PR-DUB complex. CRISPR KO of BAP1 in mouse trophoblast stem cells increases invasiveness, and this is conserved in human trophoblast stem cells.","method":"CRISPR/Cas9 KO and overexpression in mouse and human trophoblast stem cells, EMT marker analysis, invasion assays, BAP1-ASXL interaction requirement tested by mutant complementation","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined EMT phenotype and ASXL-binding dependence, single lab","pmids":["34170818"],"is_preprint":false},{"year":2017,"finding":"BAP1 inhibits cell death induced by metabolic stress (ER stress/UPR) in a deubiquitinating activity-dependent manner by repressing ATF3 and CHOP transcription; BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Bap1 KO mice are more sensitive to tunicamycin-induced renal damage.","method":"BAP1 KO mouse (tunicamycin model), ChIP at ATF3/CHOP promoters, ROS/ATP measurements, cell death assays with catalytic mutant BAP1","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at target promoters with catalytic mutant and in vivo KO mouse model, single lab","pmids":["28275095"],"is_preprint":false},{"year":2021,"finding":"BAP1 binds YY1 transcription factor and, together with YY1, occupies the promoter regions of TRAIL death receptors DR4 and DR5 to repress their transcription; catalytically inactive BAP1 fails to reduce DR4/DR5 promoter activity, indicating deubiquitinase activity is required.","method":"Co-immunoprecipitation of BAP1-YY1, ChIP at DR4/DR5 promoters, luciferase reporter assays with wt and catalytic mutant BAP1, BAP1 and YY1 knockdown with DR4/DR5 expression readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, reporter assay with catalytic mutant, single lab","pmids":["34597666"],"is_preprint":false},{"year":2022,"finding":"MBD5 and MBD6 bind to the C-terminal PHD fingers of ASXL1-3 scaffold proteins and stabilize the BAP1 complex at chromatin; depletion of MBD6 causes global loss of BAP1 chromatin occupancy and reduces BAP1-dependent gene expression and tumor growth in SCLC.","method":"Biochemical complex purification/size exclusion chromatography, mass spectrometry, ChIP-seq, RNA-seq, MBD6 depletion in SCLC cells and xenografts","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-defined interaction, ChIP-seq occupancy, and functional tumor growth readout, single lab","pmids":["36180891"],"is_preprint":false},{"year":2022,"finding":"BAP1 stabilizes SMN (survival of motor neuron protein) in fibro-adipogenic progenitors (FAPs) expressing Dpp4 by preventing SMN's ubiquitination-dependent degradation; Bap1 deletion in these cells reduces SMN levels, causing neuromuscular junction degeneration and motor neuron loss, which is rescued by ubiquitination-resistant SMN (SMNK186R).","method":"Conditional Bap1 KO in Dpp4+ FAPs (mouse), ubiquitination assays, SMN protein stability assays, neuromuscular phenotype analysis, SMNK186R rescue, cell transplantation","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with biochemical ubiquitination evidence and genetic rescue, single lab","pmids":["35603786"],"is_preprint":false},{"year":2020,"finding":"ASXL3 functions as an adaptor protein that directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), bridging the BAP1 complex to BRD4 at active enhancers in SCLC; depletion of ASXL3 reduces genome-wide H3K27Ac levels and BRD4-dependent gene expression.","method":"Size exclusion chromatography, mass spectrometry, co-immunoprecipitation, ChIP-seq, RNA-seq, ASXL3 depletion","journal":"Genome medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-defined interaction confirmed by Co-IP and ChIP-seq, single lab","pmids":["32669118"],"is_preprint":false},{"year":2020,"finding":"Wild-type ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 as part of the BAP1-ASXL1 complex to regulate a subset of FOXK1/K2 target genes involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling; C-terminally truncated mutant ASXL1 loses the ability to interact with FOXK1/K2 and dominantly inhibits the wild-type ASXL1-BAP1-TF interaction.","method":"Co-immunoprecipitation, ASXL1 mutant allele deletion, rescue experiments, gene expression analysis of FOXK1/K2 target genes","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutant allele deletion rescue, single lab","pmids":["32683582"],"is_preprint":false},{"year":2023,"finding":"BAP1 promotes osteoclast function via metabolic reprogramming; BAP1 deubiquitinase activity controls SLC7A11 expression through H2Aub occupancy at its promoter, which regulates cellular ROS and redirects mitochondrial metabolites away from the TCA cycle, both necessary for osteoclast cytoskeletal organization and bone resorption.","method":"Myeloid-specific Bap1 KO mice, bone mass phenotyping, H2Aub ChIP at SLC7A11 promoter, SLC7A11 expression analysis, metabolic profiling","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with mechanistic ChIP and metabolic readouts, single lab","pmids":["37740028"],"is_preprint":false},{"year":2020,"finding":"BAP1 maintains chromosome stability by binding and stabilizing DIDO1 (a centrosome/spindle assembly component) through deubiquitination in renal cell carcinoma cells.","method":"Co-immunoprecipitation, deubiquitination assay, chromosome stability assays, expression correlation in ccRCC tissues","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and deubiquitination assay, single lab, no independent replication","pmids":["32509391"],"is_preprint":false},{"year":2024,"finding":"BAP1 deubiquitinates MAFF (a bZIP transcription factor) to stabilize it against K48-linked ubiquitination-mediated proteasomal degradation; stabilized MAFF upregulates DUSP5, resulting in inhibition of ERK phosphorylation and suppression of colorectal cancer growth.","method":"DUB expression library screening, co-immunoprecipitation, deubiquitination assay, DUSP5 expression analysis, ERK phosphorylation measurements, in vitro and in vivo tumor growth assays","journal":"European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DUB screen plus biochemical validation with downstream pathway readout, single lab","pmids":["39151323"],"is_preprint":false},{"year":2024,"finding":"BAP1 protects against disulfidptosis (a cell death mode caused by cystine accumulation and NADPH depletion) by repressing SLC7A11 expression via H2Aub regulation, reducing intracellular cystine uptake; overexpressing SLC7A11 or adding exogenous cystine counteracts BAP1's protective effect, and BAP1 loss also lowers NADPH levels.","method":"Cell death inhibitor profiling, disulfide bond accumulation assays, SLC7A11 KO and overexpression, cystine uptake assays, NADP+/NADPH measurements","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell death and metabolic assays with genetic rescue, single lab","pmids":["39266549"],"is_preprint":false},{"year":2025,"finding":"FOXO3a transcriptionally regulates BAP1 by binding to the BAP1 promoter; BAP1 in turn deubiquitinates FOXO3a (at K48 sites) via its UCH domain to stabilize FOXO3a. BAP1 overexpression increases SLC7A11 repression and GPX4 suppression via H2Aub, promoting neuronal ferroptosis after subarachnoid hemorrhage.","method":"Luciferase reporter assays, co-immunoprecipitation, deubiquitination assay, ChIP at SLC7A11 promoter, BAP1 overexpression/siRNA knockdown, mouse SAH model with lentiviral shBAP1","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deubiquitination assay, promoter reporter, ChIP, and in vivo model, single lab","pmids":["40080966"],"is_preprint":false},{"year":2024,"finding":"ATF2 transcription factor regulates BAP1 expression by binding to the BAP1 promoter; BAP1 enhances P53 stability by reducing its proteasome-mediated degradation, and elevated P53 promotes neuronal apoptosis via the P53 pathway after subarachnoid hemorrhage.","method":"Luciferase assay (ATF2 binding to BAP1 promoter), co-immunoprecipitation, P53 ubiquitination/stability assays, BAP1 shRNA in SAH mouse model","journal":"Stroke","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and promoter assay, single lab, limited mechanistic depth on BAP1-P53 deubiquitination","pmids":["38965653"],"is_preprint":false},{"year":2019,"finding":"SLC7A11 repression by BAP1 occurs independently of NRF2 and ATF4 transcription factors; both BAP1 (which decreases H2Aub) and PRC1 (a major H2Aub E3 ligase that increases H2Aub) repress SLC7A11 expression, suggesting dynamic regulation of H2Aub is required for SLC7A11 repression; BAP1 promotes ferroptosis induced by class I FIN (erastin) but not class II FIN (RSL3).","method":"H2Aub ChIP at SLC7A11 promoter, NRF2/ATF4 genetic knockdown, ferroptosis assays with class I and II inducers","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with genetic controls and mechanistic class-specific ferroptosis assays, extends prior work, single lab","pmids":["30907299"],"is_preprint":false},{"year":2022,"finding":"Eleven high-occurrence non-catalytic mutations within BAP1's UCH domain significantly destabilize the domain, increase aggregation propensity, and cause allosteric destabilization at sites distant from the catalytic site as revealed by hydrogen-deuterium exchange mass spectrometry, providing a mechanism for how non-catalytic mutations impair BAP1 function.","method":"Multiplex spectroscopic analysis, thermodynamic assays, HDX-MS, aggregation assays for UCH domain mutants","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — rigorous biophysical and structural HDX-MS analysis with multiple orthogonal methods, single lab","pmids":["35317997"],"is_preprint":false},{"year":2021,"finding":"BAP1 deubiquitinase activity is required for ROS homeostasis, cell motility, and mitochondrial activity in mesothelioma cells; catalytically dead BAP1 fails to rescue these phenotypes. Monitoring intracellular ROS levels partly restores morphology and mitochondrial activity in BAP1-inactivated cells.","method":"Quantitative mass spectrometry (proteome), gene expression arrays, functional assays in BAP1-null/wt/catalytic-dead mesothelioma lines, ROS measurements","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant complementation with multiple proteomic and functional readouts, single lab","pmids":["29069806"],"is_preprint":false},{"year":2015,"finding":"A BAP1 point mutation F170I (found in esophageal squamous cell carcinoma) markedly suppresses deubiquitinase and auto-deubiquitinase activity and causes cytoplasmic mislocalization of BAP1, preventing its nuclear tumor suppressor function; wild-type BAP1 induces TCEAL7 expression, which the F170I mutant cannot.","method":"Deubiquitinase activity assay of mutant vs wt BAP1, subcellular fractionation/localization studies, gene expression microarray, TCEAL7 induction assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro catalytic assay plus localization and transcriptional readout for cancer mutant, single lab","pmids":["26081045"],"is_preprint":false},{"year":2021,"finding":"BAP1 has a cell-intrinsic role in B lymphocyte development: Bap1 deletion in the B cell lineage causes depletion of large pre-B cells, transitional B cells, and mature B cells with broad transcriptional changes linked to cell cycle regulation, and BAP1 loss increases histone H2AK119ub levels at gene regulatory regions in pre-B cells.","method":"Conditional Bap1 KO (Bap1fl/fl mb1-Cre) mouse, flow cytometry of B cell populations, RNA-seq, ChIP-seq for BAP1 binding and H2AK119ub","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype and genome-wide mechanistic data, single lab","pmids":["33912157"],"is_preprint":false},{"year":2021,"finding":"Co-occurrence of BAP1 deficiency and SF3B1 hotspot mutation induces cellular senescence and growth arrest in uveal melanoma cells, associated with downregulation of DNA-repair genes and impaired DNA damage response; this provides a mechanistic explanation for the mutual exclusivity of these mutations in uveal melanoma.","method":"Isogenic UM cell lines with BAP1 deletion and SF3B1 mutation, transcriptome analysis, DNA damage response assays, zebrafish xenograft invasion models, mouse xenograft growth assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic lines with transcriptomic and functional phenotypic readouts, single lab","pmids":["34706158"],"is_preprint":false}],"current_model":"BAP1 is a nuclear (and partially cytoplasmic/ER-resident) deubiquitinase that removes monoubiquitin from histone H2AK119 (activated by the ASXL1/2/3 DEUBAD domain in the PR-DUB complex, as revealed by cryo-EM structure) to safeguard transcriptionally active genes from PRC1-mediated silencing; it also deubiquitinates and stabilizes multiple non-histone substrates including IP3R3 (at the ER, promoting Ca2+-driven apoptosis), HCF-1, KLF5, PTEN, LATS, HIF-1α, MCRS1, DIDO1, INO80, SMN, MAFF, and FOXO3a, and represses SLC7A11 transcription through H2Aub to promote ferroptosis; its nuclear import is mediated by transportin-1 via a PY-NLS, and IR-induced phosphorylation recruits it to DSBs to facilitate homologous recombination repair."},"narrative":{"mechanistic_narrative":"BAP1 is a UCH-family deubiquitinase that operates principally on chromatin to oppose Polycomb-mediated silencing, while also stabilizing a wide range of non-histone substrates to control cell proliferation, metabolic stress responses, and programmed cell death [PMID:26739236, PMID:30664650]. As the catalytic subunit of the PR-DUB/BAP1 core complex, its C-terminal extension auto-recruits it to nucleosomes and is allosterically activated by the DEUBAD domains of ASXL1/2/3 to specifically remove monoubiquitin from H2AK119, a reaction it cannot perform on DNA-damage-dependent H2A K13/K15 ubiquitination [PMID:26739236]; a cryo-EM structure of the BAP1–ASXL1 DEUBAD complex on a H2AK119Ub nucleosome explains how the enzyme restructures the nucleosome to achieve this specificity and rationalizes >50 cancer-associated mutations [PMID:37556531]. Rather than driving repression, the assembled BAP1 complex safeguards transcriptionally active genes against PRC1-mediated silencing [PMID:30664650], with complex chromatin occupancy stabilized by MBD5/MBD6 binding to ASXL PHD fingers and bridged to active enhancers via an ASXL3–BRD4 interaction [PMID:36180891, PMID:32669118]. Through H2Aub regulation at the SLC7A11 promoter, BAP1 represses the cystine transporter to elevate lipid peroxidation and promote ferroptosis as a tumor-suppressor output [PMID:30202049, PMID:30907299]. Beyond chromatin, BAP1 deubiquitinates and stabilizes numerous substrates including HCF-1, KLF5, PTEN, LATS, HIF-1α, and SMN, coupling its activity to cell-cycle control, Hippo and AKT signaling, hypoxic adaptation, and tissue maintenance [PMID:19815555, PMID:26419610, PMID:33155366, PMID:31988076, PMID:36656861, PMID:35603786]. It localizes to the ER to deubiquitinate and stabilize IP3R3, sustaining Ca2+ flux that promotes apoptosis [PMID:28614305], and is required at DNA double-strand breaks, where catalytic activity and IR-induced phosphorylation drive its recruitment to facilitate BRCA1/RAD51-dependent homologous recombination [PMID:24347639]. Its predominantly nuclear function depends on Transportin-1 recognition of an atypical C-terminal PY-NLS that counteracts UBE2O-mediated cytosolic retention [PMID:35446349].","teleology":[{"year":2009,"claim":"Establishing BAP1 as a deubiquitinase with a defined substrate addressed whether its growth-regulatory role was enzymatic, identifying HCF-1 as the first physiological substrate.","evidence":"MS co-purification, Co-IP, ubiquitin chain-linkage analysis, and HBM-mutant rescue","pmids":["19815555"],"confidence":"High","gaps":["Did not define the chromatin/histone substrate","Mechanism of growth regulation downstream of HCF-1 unresolved"]},{"year":2013,"claim":"Linking BAP1 to DNA repair answered whether it acts in genome maintenance, showing both catalysis and IR-induced phosphorylation are needed for recruitment to double-strand breaks and homologous recombination.","evidence":"DT40 knockout, IR sensitivity, BRCA1/RAD51 foci imaging, I-SceI DSB assay, phosphomutant analysis","pmids":["24347639"],"confidence":"High","gaps":["Relevant deubiquitination substrate at DSBs not identified","Kinase responsible for IR-induced phosphorylation unknown"]},{"year":2015,"claim":"Multiple studies expanded the non-histone substrate repertoire and connected BAP1 loss to Polycomb mark dysregulation, defining how it controls proliferation and chromosome stability.","evidence":"Conditional Bap1 KO mice with ChIP-seq and epistasis; genome-wide DUB screens with Co-IP, deubiquitination assays, and xenograft rescue (KLF5, MCRS1)","pmids":["26437366","26419610","26300492"],"confidence":"High","gaps":["Direct vs indirect effects on H3K27me3/EZH2 not fully separated","Whether substrate stabilization is cell-type specific unclear"]},{"year":2016,"claim":"Biochemical reconstitution defined the catalytic mechanism, showing BAP1's C-terminal extension auto-recruits it to nucleosomes and ASXL DEUBAD domains activate H2AK119-specific deubiquitination.","evidence":"In vitro reconstitution with purified nucleosomes, C-terminal mutagenesis, and substrate specificity assays (H2AK119 vs K13/15)","pmids":["26739236"],"confidence":"High","gaps":["Atomic basis of specificity not yet resolved","Role of complex on native chromatin not addressed in vitro"]},{"year":2017,"claim":"Identifying ER-localized IP3R3 deubiquitination and ER-stress transcriptional repression broadened BAP1 beyond the nucleus, linking it to Ca2+-driven apoptosis and UPR control.","evidence":"Subcellular fractionation, Co-IP, deubiquitylation and Ca2+ flux assays; ChIP at ATF3/CHOP promoters in Bap1 KO mice","pmids":["28614305","28275095"],"confidence":"Medium","gaps":["How BAP1 partitions between ER and nucleus unresolved","ER targeting determinants not mapped"]},{"year":2018,"claim":"Work on the SLC7A11/ferroptosis axis and additional complex interactions established a metabolic tumor-suppressor output and refined the complex's repertoire (HMGB1/HDAC1, DRED, ASXL1-MT leukemia).","evidence":"ChIP, deubiquitinase-dead mutants, cystine uptake and lipid peroxidation assays, in vivo tumor models; Co-IP and ubiquitylation assays","pmids":["30202049","34815344","30463901","30013160"],"confidence":"Medium","gaps":["Direct vs indirect H2Aub effects on SLC7A11 not fully separated","Tissue-specificity of complex composition unclear"]},{"year":2019,"claim":"Reframing the BAP1 complex as a transcriptional activator overturned its presumed silencing role, showing it safeguards active genes against PRC1, and clarified SLC7A11 regulation requires dynamic H2Aub.","evidence":"Isogenic CRISPR lines with ChIP-seq/RNA-seq and catalytic-mutant complementation; H2Aub ChIP with NRF2/ATF4 knockdown","pmids":["30664650","30907299","31657441"],"confidence":"High","gaps":["How dynamic H2Aub turnover is coordinated with PRC1 unresolved","Genome-wide rules for activation vs repression unclear"]},{"year":2021,"claim":"A series of studies defined further stabilized substrates (PTEN, LATS, HIF-1α, INO80) and physiological roles in B-cell development and mesothelioma ROS homeostasis, mapping BAP1 onto major signaling and stress pathways.","evidence":"Co-IP, deubiquitination assays with mutagenesis, conditional KO mice, proteomics, and fork/restart assays","pmids":["33155366","31988076","36656861","33658435","33912157","29069806","34597666"],"confidence":"Medium","gaps":["Many substrate interactions rest on single-lab Co-IP","Direct vs indirect contributions to each pathway not always separated"]},{"year":2022,"claim":"Defining the PY-NLS/Transportin-1 import mechanism and chromatin-stabilizing MBD5/6 interactions explained how BAP1 reaches and persists on its nuclear targets, while HDX-MS clarified non-catalytic cancer mutations.","evidence":"Co-IP, nuclear import assays, NLS/dimerization mutagenesis; complex purification with ChIP-seq; HDX-MS on UCH-domain mutants","pmids":["35446349","36180891","35317997"],"confidence":"Medium","gaps":["Regulation of UBE2O-driven cytosolic retention in vivo unclear","Functional consequence of aggregation-prone mutants in cells not fully tested"]},{"year":2023,"claim":"The cryo-EM structure of BAP1–ASXL1 on a H2AK119Ub nucleosome provided the atomic basis for substrate specificity and rationalized cancer mutations, completing the mechanistic picture of the chromatin reaction.","evidence":"Cryo-EM structure with biochemical deubiquitination, structure-guided mutagenesis, and cellular validation","pmids":["37556531"],"confidence":"High","gaps":["Structures with ASXL2/ASXL3 not determined","Dynamics of nucleosome restructuring not captured"]},{"year":2025,"claim":"Recent work added regulatory feedback (FOXO3a) and disease-context outputs (disulfidptosis, neuronal ferroptosis/apoptosis), but a unified model integrating chromatin, substrate, and feedback layers is still incomplete.","evidence":"Co-IP, deubiquitination assays, promoter reporters, ChIP, and in vivo models","pmids":["40080966","39266549","39151323"],"confidence":"Medium","gaps":["Hierarchy among the many proposed substrates/outputs unresolved","Context-dependence of pro- vs anti-death roles unclear"]},{"year":null,"claim":"How a single deubiquitinase coordinately selects among its chromatin and dozens of non-histone substrates in a tissue- and context-specific manner, and how this dictates its tumor-suppressor versus cell-death outputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative substrate hierarchy","Determinants of cytoplasmic vs nuclear vs ER function not integrated","In vivo relevance of many single-lab substrates untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,5,8,15,16,17,24]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,5,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,7,21,22]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[5,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8,15,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,18,36]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,36]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,5,7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,7,21,22]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,13,30]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,8,15,16,24]}],"complexes":["PR-DUB / BAP1 core complex (BAP1-ASXL1/2/3)","BAP1/HCF-1 complex","DRED repressor complex"],"partners":["ASXL1","ASXL2","ASXL3","HCF-1","MBD6","INO80","IP3R3","BRD4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96QZ7","full_name":"Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1","aliases":["Atrophin-1-interacting protein 3","AIP-3","BAI1-associated protein 1","BAP-1","Membrane-associated guanylate kinase inverted 1","MAGI-1","Trinucleotide repeat-containing gene 19 protein","WW domain-containing protein 3","WWP3"],"length_aa":1491,"mass_kda":164.6,"function":"Plays a role in coupling actin fibers to cell junctions in endothelial cells, via its interaction with AMOTL2 and CDH5 (By similarity). May regulate acid-induced ASIC3 currents by modulating its expression at the cell surface (By similarity)","subcellular_location":"Cell junction, tight junction; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96QZ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BAP1","classification":"Not Classified","n_dependent_lines":682,"n_total_lines":1208,"dependency_fraction":0.5645695364238411},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BAP1","total_profiled":1310},"omim":[{"mim_id":"619762","title":"KURY-ISIDOR SYNDROME; KURIS","url":"https://www.omim.org/entry/619762"},{"mim_id":"619458","title":"METHYL-CpG-BINDING DOMAIN PROTEIN 6; MBD6","url":"https://www.omim.org/entry/619458"},{"mim_id":"618813","title":"TUBULIN TYROSINE LIGASE-LIKE 7; TTLL7","url":"https://www.omim.org/entry/618813"},{"mim_id":"617649","title":"UBIQUITIN-CONJUGATING ENZYME E2 O; UBE2O","url":"https://www.omim.org/entry/617649"},{"mim_id":"617346","title":"ATP/GTP-BINDING PROTEIN-LIKE 3; AGBL3","url":"https://www.omim.org/entry/617346"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BAP1"},"hgnc":{"alias_symbol":["hucep-6","KIAA0272","UCHL2"],"prev_symbol":[]},"alphafold":{"accession":"Q96QZ7","domains":[{"cath_id":"2.30.42.10","chopping":"12-53_60-142_192-213","consensus_level":"high","plddt":82.7526,"start":12,"end":213},{"cath_id":"2.20.70","chopping":"364-401","consensus_level":"medium","plddt":79.8232,"start":364,"end":401},{"cath_id":"2.30.42.10","chopping":"464-565","consensus_level":"high","plddt":87.1854,"start":464,"end":565},{"cath_id":"2.30.42.10","chopping":"641-722","consensus_level":"high","plddt":84.7895,"start":641,"end":722},{"cath_id":"2.30.42.10","chopping":"838-925","consensus_level":"medium","plddt":89.7289,"start":838,"end":925},{"cath_id":"2.30.42.10","chopping":"998-1017_1034-1092","consensus_level":"medium","plddt":84.7994,"start":998,"end":1092},{"cath_id":"2.30.42.10","chopping":"1152-1232","consensus_level":"high","plddt":91.4384,"start":1152,"end":1232}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QZ7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QZ7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QZ7-F1-predicted_aligned_error_v6.png","plddt_mean":59.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BAP1","jax_strain_url":"https://www.jax.org/strain/search?query=BAP1"},"sequence":{"accession":"Q96QZ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QZ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QZ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QZ7"}},"corpus_meta":[{"pmid":"30202049","id":"PMC_30202049","title":"BAP1 links metabolic regulation of ferroptosis to tumour suppression.","date":"2018","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30202049","citation_count":839,"is_preprint":false},{"pmid":"23550303","id":"PMC_23550303","title":"BAP1 and cancer.","date":"2013","source":"Nature reviews. Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23550303","citation_count":518,"is_preprint":false},{"pmid":"28614305","id":"PMC_28614305","title":"BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28614305","citation_count":334,"is_preprint":false},{"pmid":"24347639","id":"PMC_24347639","title":"Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24347639","citation_count":308,"is_preprint":false},{"pmid":"26437366","id":"PMC_26437366","title":"Loss of BAP1 function leads to EZH2-dependent transformation.","date":"2015","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26437366","citation_count":299,"is_preprint":false},{"pmid":"22935333","id":"PMC_22935333","title":"BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs.","date":"2012","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22935333","citation_count":240,"is_preprint":false},{"pmid":"32690542","id":"PMC_32690542","title":"Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer.","date":"2020","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/32690542","citation_count":238,"is_preprint":false},{"pmid":"19815555","id":"PMC_19815555","title":"The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19815555","citation_count":226,"is_preprint":false},{"pmid":"23277170","id":"PMC_23277170","title":"Tumours associated with BAP1 mutations.","date":"2013","source":"Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23277170","citation_count":224,"is_preprint":false},{"pmid":"30517737","id":"PMC_30517737","title":"Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.","date":"2018","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/30517737","citation_count":206,"is_preprint":false},{"pmid":"26419610","id":"PMC_26419610","title":"BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26419610","citation_count":180,"is_preprint":false},{"pmid":"26739236","id":"PMC_26739236","title":"BAP1/ASXL1 recruitment and activation for H2A deubiquitination.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26739236","citation_count":169,"is_preprint":false},{"pmid":"28473526","id":"PMC_28473526","title":"Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade.","date":"2017","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/28473526","citation_count":148,"is_preprint":false},{"pmid":"32877777","id":"PMC_32877777","title":"BAP1: Not just a BRCA1-associated protein.","date":"2020","source":"Cancer treatment reviews","url":"https://pubmed.ncbi.nlm.nih.gov/32877777","citation_count":144,"is_preprint":false},{"pmid":"33462414","id":"PMC_33462414","title":"Roles and mechanisms of BAP1 deubiquitinase in tumor suppression.","date":"2021","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/33462414","citation_count":136,"is_preprint":false},{"pmid":"28482042","id":"PMC_28482042","title":"BAP1 mutations in high-grade meningioma: implications for patient care.","date":"2017","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28482042","citation_count":133,"is_preprint":false},{"pmid":"30664650","id":"PMC_30664650","title":"BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30664650","citation_count":126,"is_preprint":false},{"pmid":"30907299","id":"PMC_30907299","title":"Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1.","date":"2019","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/30907299","citation_count":119,"is_preprint":false},{"pmid":"26300218","id":"PMC_26300218","title":"Clear Cell Renal Cell Carcinoma Subtypes Identified by BAP1 and PBRM1 Expression.","date":"2015","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/26300218","citation_count":116,"is_preprint":false},{"pmid":"30013160","id":"PMC_30013160","title":"Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30013160","citation_count":111,"is_preprint":false},{"pmid":"21484256","id":"PMC_21484256","title":"An emerging model for BAP1's role in regulating cell cycle progression.","date":"2011","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/21484256","citation_count":102,"is_preprint":false},{"pmid":"23867514","id":"PMC_23867514","title":"PBRM1 and BAP1 as novel targets for renal cell carcinoma.","date":"2013","source":"Cancer journal (Sudbury, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/23867514","citation_count":98,"is_preprint":false},{"pmid":"28409567","id":"PMC_28409567","title":"SF3B1 and BAP1 mutations in blue nevus-like melanoma.","date":"2017","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/28409567","citation_count":85,"is_preprint":false},{"pmid":"28275095","id":"PMC_28275095","title":"BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28275095","citation_count":83,"is_preprint":false},{"pmid":"25080371","id":"PMC_25080371","title":"Germline BAP1 mutations predispose also to multiple basal cell carcinomas.","date":"2014","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25080371","citation_count":83,"is_preprint":false},{"pmid":"29988936","id":"PMC_29988936","title":"Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma.","date":"2018","source":"Journal of current ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/29988936","citation_count":82,"is_preprint":false},{"pmid":"27235536","id":"PMC_27235536","title":"Gene of the month: BAP1.","date":"2016","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27235536","citation_count":77,"is_preprint":false},{"pmid":"23147254","id":"PMC_23147254","title":"The ASXL-BAP1 axis: new factors in myelopoiesis, cancer and epigenetics.","date":"2012","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/23147254","citation_count":72,"is_preprint":false},{"pmid":"28122578","id":"PMC_28122578","title":"BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma.","date":"2017","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28122578","citation_count":71,"is_preprint":false},{"pmid":"27859460","id":"PMC_27859460","title":"Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma.","date":"2017","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/27859460","citation_count":67,"is_preprint":false},{"pmid":"27181379","id":"PMC_27181379","title":"CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27181379","citation_count":62,"is_preprint":false},{"pmid":"28713672","id":"PMC_28713672","title":"BAP1, a tumor suppressor gene driving malignant mesothelioma.","date":"2017","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28713672","citation_count":58,"is_preprint":false},{"pmid":"36253570","id":"PMC_36253570","title":"PBRM1, SETD2 and BAP1 - the trinity of 3p in clear cell renal cell carcinoma.","date":"2022","source":"Nature reviews. Urology","url":"https://pubmed.ncbi.nlm.nih.gov/36253570","citation_count":56,"is_preprint":false},{"pmid":"25479927","id":"PMC_25479927","title":"BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations.","date":"2014","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25479927","citation_count":56,"is_preprint":false},{"pmid":"35459788","id":"PMC_35459788","title":"Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma.","date":"2022","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/35459788","citation_count":56,"is_preprint":false},{"pmid":"27718540","id":"PMC_27718540","title":"Germline BAP1 alterations in familial uveal melanoma.","date":"2016","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27718540","citation_count":54,"is_preprint":false},{"pmid":"31233225","id":"PMC_31233225","title":"BRCA1-associated protein (BAP1)-inactivated melanocytic tumors.","date":"2019","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31233225","citation_count":53,"is_preprint":false},{"pmid":"32669118","id":"PMC_32669118","title":"ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer.","date":"2020","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32669118","citation_count":51,"is_preprint":false},{"pmid":"33210135","id":"PMC_33210135","title":"BAP1-Mutated Clear Cell Renal Cell Carcinoma.","date":"2021","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33210135","citation_count":48,"is_preprint":false},{"pmid":"23977234","id":"PMC_23977234","title":"A BAP1 mutation in a Danish family predisposes to uveal melanoma and other cancers.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23977234","citation_count":47,"is_preprint":false},{"pmid":"33903674","id":"PMC_33903674","title":"Estimation of the timing of BAP1 mutation in uveal melanoma progression.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33903674","citation_count":47,"is_preprint":false},{"pmid":"33446574","id":"PMC_33446574","title":"Roles of the BAP1 Tumor Suppressor in Cell Metabolism.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33446574","citation_count":46,"is_preprint":false},{"pmid":"37009801","id":"PMC_37009801","title":"BAP1 as a guardian of genome stability: implications in human cancer.","date":"2023","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37009801","citation_count":46,"is_preprint":false},{"pmid":"37607989","id":"PMC_37607989","title":"Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome.","date":"2023","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/37607989","citation_count":43,"is_preprint":false},{"pmid":"32206571","id":"PMC_32206571","title":"BAP1: role in carcinogenesis and clinical implications.","date":"2020","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32206571","citation_count":41,"is_preprint":false},{"pmid":"37556531","id":"PMC_37556531","title":"Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37556531","citation_count":41,"is_preprint":false},{"pmid":"34170818","id":"PMC_34170818","title":"BAP1/ASXL complex modulation regulates epithelial-mesenchymal transition during trophoblast differentiation and invasion.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34170818","citation_count":41,"is_preprint":false},{"pmid":"29686263","id":"PMC_29686263","title":"BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29686263","citation_count":40,"is_preprint":false},{"pmid":"26300492","id":"PMC_26300492","title":"Stabilization of MCRS1 by BAP1 prevents chromosome instability in renal cell carcinoma.","date":"2015","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26300492","citation_count":40,"is_preprint":false},{"pmid":"33155366","id":"PMC_33155366","title":"BAP1 suppresses prostate cancer progression by deubiquitinating and stabilizing PTEN.","date":"2020","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33155366","citation_count":36,"is_preprint":false},{"pmid":"32185138","id":"PMC_32185138","title":"Identifying BAP1 Mutations in Clear-Cell Renal Cell Carcinoma by CT Radiomics: Preliminary Findings.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32185138","citation_count":36,"is_preprint":false},{"pmid":"26885612","id":"PMC_26885612","title":"BAP1 suppresses lung cancer progression and is inhibited by miR-31.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26885612","citation_count":36,"is_preprint":false},{"pmid":"27114369","id":"PMC_27114369","title":"Loss of expression of BAP1 is very rare in non-small cell lung carcinoma.","date":"2016","source":"Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27114369","citation_count":34,"is_preprint":false},{"pmid":"30463901","id":"PMC_30463901","title":"BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression.","date":"2018","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/30463901","citation_count":33,"is_preprint":false},{"pmid":"25687217","id":"PMC_25687217","title":"Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients.","date":"2015","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25687217","citation_count":32,"is_preprint":false},{"pmid":"35932824","id":"PMC_35932824","title":"The expanding role of BAP1 in clear cell renal cell carcinoma.","date":"2022","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35932824","citation_count":31,"is_preprint":false},{"pmid":"32371459","id":"PMC_32371459","title":"CCR5 blockade inflames antitumor immunity in BAP1-mutant clear cell renal cell carcinoma.","date":"2020","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32371459","citation_count":31,"is_preprint":false},{"pmid":"25521456","id":"PMC_25521456","title":"BAP1 has a survival role in cutaneous melanoma.","date":"2014","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25521456","citation_count":31,"is_preprint":false},{"pmid":"31657441","id":"PMC_31657441","title":"BAP1 promotes stalled fork restart and cell survival via INO80 in response to replication stress.","date":"2019","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/31657441","citation_count":29,"is_preprint":false},{"pmid":"32683582","id":"PMC_32683582","title":"Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network.","date":"2020","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/32683582","citation_count":29,"is_preprint":false},{"pmid":"31988076","id":"PMC_31988076","title":"The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma.","date":"2020","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31988076","citation_count":29,"is_preprint":false},{"pmid":"34815344","id":"PMC_34815344","title":"BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34815344","citation_count":28,"is_preprint":false},{"pmid":"37740028","id":"PMC_37740028","title":"BAP1 promotes osteoclast function by metabolic reprogramming.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37740028","citation_count":26,"is_preprint":false},{"pmid":"36656861","id":"PMC_36656861","title":"BAP1 is a novel regulator of HIF-1α.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36656861","citation_count":25,"is_preprint":false},{"pmid":"33516665","id":"PMC_33516665","title":"BAP1 antagonizes WWP1-mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression.","date":"2021","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33516665","citation_count":25,"is_preprint":false},{"pmid":"29069806","id":"PMC_29069806","title":"Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29069806","citation_count":24,"is_preprint":false},{"pmid":"25972334","id":"PMC_25972334","title":"Loss of BAP1 Expression in Basal Cell Carcinomas in Patients With Germline BAP1 Mutations.","date":"2015","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25972334","citation_count":24,"is_preprint":false},{"pmid":"26517537","id":"PMC_26517537","title":"Functional Link between BRCA1 and BAP1 through Histone H2A, Heterochromatin and DNA Damage Response.","date":"2016","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/26517537","citation_count":23,"is_preprint":false},{"pmid":"34706158","id":"PMC_34706158","title":"Co-occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence.","date":"2021","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34706158","citation_count":23,"is_preprint":false},{"pmid":"26774355","id":"PMC_26774355","title":"A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.","date":"2015","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26774355","citation_count":23,"is_preprint":false},{"pmid":"34857909","id":"PMC_34857909","title":"Novel insights into the BAP1-inactivated melanocytic tumor.","date":"2021","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/34857909","citation_count":21,"is_preprint":false},{"pmid":"39266549","id":"PMC_39266549","title":"Tumor suppressor BAP1 suppresses disulfidptosis through the regulation of SLC7A11 and NADPH levels.","date":"2024","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/39266549","citation_count":19,"is_preprint":false},{"pmid":"31159579","id":"PMC_31159579","title":"BAP1 in solid tumors.","date":"2019","source":"Future oncology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31159579","citation_count":19,"is_preprint":false},{"pmid":"26081045","id":"PMC_26081045","title":"Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma.","date":"2015","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/26081045","citation_count":19,"is_preprint":false},{"pmid":"38150154","id":"PMC_38150154","title":"ITGB2-ICAM1 axis promotes liver metastasis in BAP1-mutated uveal melanoma with retained hypoxia and ECM signatures.","date":"2023","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/38150154","citation_count":17,"is_preprint":false},{"pmid":"37880686","id":"PMC_37880686","title":"Preventive and therapeutic opportunities: targeting BAP1 and/or HMGB1 pathways to diminish the burden of mesothelioma.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37880686","citation_count":17,"is_preprint":false},{"pmid":"36180891","id":"PMC_36180891","title":"MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer.","date":"2022","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/36180891","citation_count":17,"is_preprint":false},{"pmid":"36292588","id":"PMC_36292588","title":"Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36292588","citation_count":17,"is_preprint":false},{"pmid":"36657447","id":"PMC_36657447","title":"Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.","date":"2023","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36657447","citation_count":17,"is_preprint":false},{"pmid":"36318367","id":"PMC_36318367","title":"BAP1 in cancer: epigenetic stability and genome integrity.","date":"2022","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36318367","citation_count":16,"is_preprint":false},{"pmid":"33800007","id":"PMC_33800007","title":"Intratumor Heterogeneity in Uveal Melanoma BAP-1 Expression.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33800007","citation_count":16,"is_preprint":false},{"pmid":"34347929","id":"PMC_34347929","title":"The AMP-dependent kinase pathway is upregulated in BAP1 mutant uveal melanoma.","date":"2021","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/34347929","citation_count":15,"is_preprint":false},{"pmid":"38759225","id":"PMC_38759225","title":"Multiple Onychopapillomas and BAP1 Tumor Predisposition Syndrome.","date":"2024","source":"JAMA dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/38759225","citation_count":15,"is_preprint":false},{"pmid":"32509391","id":"PMC_32509391","title":"BAP1 maintains chromosome stability by stabilizing DIDO1 in renal cell carcinoma.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32509391","citation_count":15,"is_preprint":false},{"pmid":"35603786","id":"PMC_35603786","title":"Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/35603786","citation_count":15,"is_preprint":false},{"pmid":"35046531","id":"PMC_35046531","title":"Pyruvate dehydrogenase inactivation causes glycolytic phenotype in BAP1 mutant uveal melanoma.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35046531","citation_count":15,"is_preprint":false},{"pmid":"33529461","id":"PMC_33529461","title":"BAP1 promotes viability and migration of ECA109 cells through KLF5/CyclinD1/FGF-BP1.","date":"2021","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/33529461","citation_count":14,"is_preprint":false},{"pmid":"33866194","id":"PMC_33866194","title":"The spectrum of tumors harboring BAP1 gene alterations.","date":"2021","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33866194","citation_count":14,"is_preprint":false},{"pmid":"35317997","id":"PMC_35317997","title":"Impacts of Cancer-associated Mutations on the Structure-Activity Relationship of BAP1.","date":"2022","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35317997","citation_count":14,"is_preprint":false},{"pmid":"33658435","id":"PMC_33658435","title":"CHIP and BAP1 Act in Concert to Regulate INO80 Ubiquitination and Stability for DNA Replication.","date":"2021","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/33658435","citation_count":14,"is_preprint":false},{"pmid":"40080966","id":"PMC_40080966","title":"FOXO3a-BAP1 axis regulates neuronal ferroptosis in early brain injury after subarachnoid hemorrhage.","date":"2025","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/40080966","citation_count":13,"is_preprint":false},{"pmid":"35446349","id":"PMC_35446349","title":"Tumor suppressor BAP1 nuclear import is governed by transportin-1.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35446349","citation_count":13,"is_preprint":false},{"pmid":"36669126","id":"PMC_36669126","title":"BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification.","date":"2023","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/36669126","citation_count":13,"is_preprint":false},{"pmid":"33912157","id":"PMC_33912157","title":"Regulation of B Lymphocyte Development by Histone H2A Deubiquitinase BAP1.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33912157","citation_count":13,"is_preprint":false},{"pmid":"34737422","id":"PMC_34737422","title":"BAP1 loss augments sensitivity to BET inhibitors in cancer cells.","date":"2021","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/34737422","citation_count":13,"is_preprint":false},{"pmid":"38965653","id":"PMC_38965653","title":"ATF2/BAP1 Axis Mediates Neuronal Apoptosis After Subarachnoid Hemorrhage via P53 Pathway.","date":"2024","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/38965653","citation_count":12,"is_preprint":false},{"pmid":"39151323","id":"PMC_39151323","title":"BAP1-mediated MAFF deubiquitylation regulates tumor growth and is associated with adverse outcomes in colorectal cancer.","date":"2024","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/39151323","citation_count":12,"is_preprint":false},{"pmid":"35945149","id":"PMC_35945149","title":"Diagnostic capacity of BAP1 and MTAP in cytology from effusions and biopsy in mesothelioma.","date":"2022","source":"Journal of the American Society of Cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/35945149","citation_count":12,"is_preprint":false},{"pmid":"34597666","id":"PMC_34597666","title":"BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34597666","citation_count":12,"is_preprint":false},{"pmid":"36754982","id":"PMC_36754982","title":"Targeting BAP1 with small compound inhibitor for colon cancer treatment.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36754982","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49574,"output_tokens":9876,"usd":0.148431,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20079,"output_tokens":4602,"usd":0.107722,"stage2_stop_reason":"end_turn"},"total_usd":0.256153,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"BAP1 represses SLC7A11 (cystine transporter) expression by reducing histone H2A ubiquitination (H2Aub) on the SLC7A11 promoter in a deubiquitinating-dependent manner, thereby inhibiting cystine uptake, elevating lipid peroxidation, and promoting ferroptosis as a tumor suppressor mechanism.\",\n      \"method\": \"Integrated transcriptomic/epigenomic analyses, ChIP assays, functional deubiquitinase-dead mutants, cystine uptake assays, lipid peroxidation measurements, and in vivo tumor models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, mutagenesis, in vitro and in vivo assays) in a single rigorous study with functional validation\",\n      \"pmids\": [\"30202049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BAP1 localizes at the endoplasmic reticulum where it binds, deubiquitylates, and stabilizes the type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), thereby modulating calcium (Ca2+) release from the ER into the cytosol and mitochondria to promote apoptosis.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, deubiquitylation assays, Ca2+ flux measurements, cellular transformation assays, and genetic models (BAP1+/- cells)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP, biochemical deubiquitylation assay, Ca2+ flux measurement, and transformation readout across multiple orthogonal methods\",\n      \"pmids\": [\"28614305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAP1 is required for efficient assembly of homologous recombination (HR) factors BRCA1 and RAD51 at ionizing radiation-induced foci; BAP1-deficient cells are sensitive to DSB-inducing agents, defective in HR-mediated gene conversion, and exhibit increased chromosomal breaks. Both catalytic activity and IR-induced phosphorylation of BAP1 are required for its recruitment to DSB sites and for DNA repair.\",\n      \"method\": \"RNAi screen, gene knockout in DT40 cells, IR sensitivity assays, immunofluorescence for BRCA1/RAD51 foci, I-SceI-induced DSB assay, phosphomutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal phenotypic readouts, site-specific DSB recruitment, and phosphomutant mechanistic follow-up\",\n      \"pmids\": [\"24347639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BAP1 interacts with host cell factor-1 (HCF-1) via an HCF-1 binding motif (HBM); HCF-1N is modified with Lys-48-linked polyubiquitin chains on its Kelch domain, and BAP1 deubiquitinates HCF-1N. This interaction is required for BAP1-mediated cell growth regulation.\",\n      \"method\": \"Mass spectrometry co-purification, co-immunoprecipitation, ubiquitin chain-linkage analysis, RNAi depletion, dominant-negative mutant overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-identified interaction confirmed by Co-IP, biochemical deubiquitination, and HBM-mutant functional rescue experiments\",\n      \"pmids\": [\"19815555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BAP1 loss in mice results in increased H3K27me3 levels, elevated EZH2 expression, and enhanced PRC2-target repression; this is mechanistically linked to a marked decrease in H4K20 monomethylation (H4K20me1), and SETD8 (the H4K20me1 methyltransferase) overexpression reduces EZH2 expression and abrogates BAP1-mutant cell proliferation.\",\n      \"method\": \"Conditional Bap1 knockout mice, ChIP-seq for histone marks, epistasis via Bap1/Ezh2 double conditional deletion, SETD8 overexpression rescue experiments\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis (double KO), ChIP-seq histone mark analysis, and rescue experiments across multiple orthogonal approaches\",\n      \"pmids\": [\"26437366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BAP1's C-terminal extension auto-recruits BAP1 to nucleosomes (in an acidic patch-independent manner), forming an unproductive initial complex that is activated by the DEUBAD domains of ASXL1, ASXL2, or ASXL3 to increase BAP1's affinity for ubiquitin on H2A and drive deubiquitination. The reaction is specific for Polycomb H2AK119 modifications and cannot deubiquitinate DNA damage-dependent H2A K13/K15 ubiquitination.\",\n      \"method\": \"Biochemical reconstitution with purified nucleosomes, mutagenesis of BAP1 C-terminal extension, DEUBAD domain binding assays, specificity assays comparing H2AK119 vs H2AK13/15 substrates\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis and substrate specificity assays demonstrating catalytic mechanism\",\n      \"pmids\": [\"26739236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of human BAP1 and the ASXL1 DEUBAD domain in complex with a H2AK119Ub nucleosome reveals the molecular interactions of BAP1 and ASXL1 with histones and DNA that restructure the nucleosome to establish specificity for H2AK119Ub; >50 cancer-associated mutations in BAP1 and ASXL1 are structurally explained as dysregulating this reaction.\",\n      \"method\": \"Cryo-EM structure determination, biochemical deubiquitination assays, mutagenesis of contact residues, cellular validation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with biochemical and cellular validation, mutagenesis of structure-guided residues\",\n      \"pmids\": [\"37556531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAP1-associated core complex (BAP1.com), containing ASXL1/2/3, functions as a transcriptional activator to safeguard transcriptionally active genes against silencing by Polycomb Repressive Complex 1 (PRC1), rather than participating in Polycomb-mediated silencing as previously proposed.\",\n      \"method\": \"CRISPR/Cas9-generated isogenic cell lines, integrative ChIP-seq/RNA-seq, catalytic mutant BAP1 complementation, H2AK119Ub profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic CRISPR lines, multiple orthogonal genomic/epigenomic methods, catalytic mutant controls\",\n      \"pmids\": [\"30664650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BAP1 acts as a deubiquitinase for KLF5; BAP1 directly interacts with KLF5 and stabilizes it via deubiquitination. KLF5 is a component of the BAP1/HCF-1 complex, which promotes cell cycle progression partly by inhibiting p27 gene expression. BAP1 knockdown inhibits tumorigenicity and lung metastasis, partially rescued by ectopic KLF5 expression.\",\n      \"method\": \"Genome-wide siRNA DUB screen, co-immunoprecipitation, in vitro deubiquitination assay, ubiquitination assay, rescue experiments, xenograft tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen hit validated with Co-IP, biochemical deubiquitination, and in vivo rescue across multiple orthogonal methods\",\n      \"pmids\": [\"26419610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BAP1 forms a trimeric protein complex with HMGB1 and histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and secretion; reduced BAP1 levels cause increased ubiquitylation and degradation of HDAC1, leading to increased HMGB1 acetylation and its active secretion, promoting mesothelial cell transformation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, serum HMGB1 acetylation measurements (ELISA), cellular transformation assays in BAP1+/- cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP of trimeric complex, biochemical ubiquitylation/acetylation assays, and in vivo transformation readout with mechanistic chain established\",\n      \"pmids\": [\"34815344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BAP1 is a component of the DRED repressor complex in erythroid cells; it maintains NCoR1 occupancy at the β-globin locus, and BAP1 inhibition massively induces γ-globin synthesis, demonstrating a role in γ-globin gene repression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assays at β-globin locus, BAP1 inhibition in erythroid cells with γ-globin expression readout\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP establishing complex occupancy, functional readout by BAP1 inhibition, single lab\",\n      \"pmids\": [\"30463901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAP1 promotes restart of hydroxyurea-induced stalled replication forks by recruiting the INO80 chromatin remodeler to stalled forks; BAP1 depletion abrogates INO80 binding at replication forks, increases RAD51 foci, and causes hypersensitivity to HU, rescued by INO80 re-expression.\",\n      \"method\": \"DNA fiber assays (fork restart), ChIP at replication forks, immunofluorescence, HU sensitivity assays, ectopic INO80 rescue\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fork restart assay, chromatin binding evidence, and genetic rescue, single lab\",\n      \"pmids\": [\"31657441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHIP (E3 ubiquitin ligase) polyubiquitinates INO80 in an Hsp70-dependent manner; BAP1 and CHIP act in concert to stabilize INO80 and promote its chromatin binding, which is required for efficient replication fork progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, half-life (cycloheximide chase) experiments, DNA fiber assays, ChIP\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitination assays and functional fork progression, single lab\",\n      \"pmids\": [\"33658435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BAP1 induces cell death via interaction with 14-3-3 protein; the BAP1-14-3-3 association releases the apoptotic inducer Bax from 14-3-3, promoting cell death through the intrinsic apoptosis pathway.\",\n      \"method\": \"Co-immunoprecipitation, Bax release assay, apoptosis assays, cell cycle analysis, xenograft tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating protein interaction and mechanistic Bax release assay, single lab\",\n      \"pmids\": [\"29686263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BAP1 binds to MCRS1 (a centrosome/spindle assembly component) and stabilizes it via deubiquitination, contributing to chromosome stability in renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, chromosome stability assays, expression correlation in ccRCC tissues\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in vitro deubiquitination assay with functional chromosome stability readout, single lab\",\n      \"pmids\": [\"26300492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BAP1 physically binds and deubiquitinates PTEN, inhibiting ubiquitination-mediated PTEN degradation and thereby stabilizing PTEN protein; this suppresses the AKT signaling pathway and prostate cancer progression, which is reversed by BAP1 knockdown and rescued by PTEN re-expression.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, knockdown/overexpression in PCa cells, AKT signaling measurements, PTEN re-expression rescue, xenograft models\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and deubiquitination assay with epistatic rescue, single lab\",\n      \"pmids\": [\"33155366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BAP1 stabilizes the LATS tumor suppressor kinase (Hippo pathway) by preventing its ubiquitin-dependent proteasomal degradation; BAP1-deficient pancreatic tumors show enhanced LATS degradation and Hippo pathway deregulation.\",\n      \"method\": \"Conditional Bap1 KO mouse model (KrasG12D background), ubiquitination/proteasome assays for LATS, histological and pathway analysis of pancreatic tumors\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with biochemical ubiquitination evidence for LATS stabilization, single lab\",\n      \"pmids\": [\"31988076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAP1 binds, deubiquitylates, and stabilizes HIF-1α during hypoxia; BAP1 interacts with the N-terminal region of HIF-1α where HIF-1α binds DNA and dimerizes with HIF-1β. BAP1 residues I675, F678, I679, and L691 in the C-terminal domain-NLS are required for HIF-1α interaction. Loss of BAP1 reduces nuclear HIF-1α levels in hypoxic cells.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitylation assays, site-directed mutagenesis of BAP1 C-terminal residues, computational docking, immunofluorescence/IHC in BAP1-null cells and mesothelioma biopsies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis, biochemical deubiquitylation, and cellular/tissue validation, single lab\",\n      \"pmids\": [\"36656861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Transportin-1 (TNPO1/Karyopherin β2) is the primary nuclear transporter of BAP1, targeting an atypical C-terminal proline-tyrosine nuclear localization signal (PY-NLS). TNPO1 binding dissociates dimeric BAP1 and sequesters monoubiquitination sites flanking the PY-NLS, counteracting UBE2O-mediated cytosolic retention of BAP1.\",\n      \"method\": \"Co-immunoprecipitation, nuclear import assays, PY-NLS mutagenesis, BAP1 dimerization analysis, UBE2O competition assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with NLS mutagenesis and functional nuclear import assay, single lab\",\n      \"pmids\": [\"35446349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutant ASXL1 (C-terminally truncated) undergoes increased monoubiquitination, which in turn increases the catalytic function of BAP1; the hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation and leukaemogenesis by removing H2AK119 ubiquitination at posterior HOXA genes and IRF8 loci.\",\n      \"method\": \"Biochemical ubiquitination assays, deubiquitinase activity assays of BAP1/ASXL1-MT complex, ChIP for H2AK119ub, haematopoietic progenitor differentiation assays, BAP1 depletion in ASXL1-MT leukemia cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical activity assays and ChIP with genetic depletion, single lab\",\n      \"pmids\": [\"30013160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAP1 downregulation is essential to trigger epithelial-mesenchymal transition (EMT) during trophoblast differentiation; BAP1's function in suppressing EMT is dependent on its binding to ASXL1/2 proteins to form the PR-DUB complex. CRISPR KO of BAP1 in mouse trophoblast stem cells increases invasiveness, and this is conserved in human trophoblast stem cells.\",\n      \"method\": \"CRISPR/Cas9 KO and overexpression in mouse and human trophoblast stem cells, EMT marker analysis, invasion assays, BAP1-ASXL interaction requirement tested by mutant complementation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined EMT phenotype and ASXL-binding dependence, single lab\",\n      \"pmids\": [\"34170818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BAP1 inhibits cell death induced by metabolic stress (ER stress/UPR) in a deubiquitinating activity-dependent manner by repressing ATF3 and CHOP transcription; BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Bap1 KO mice are more sensitive to tunicamycin-induced renal damage.\",\n      \"method\": \"BAP1 KO mouse (tunicamycin model), ChIP at ATF3/CHOP promoters, ROS/ATP measurements, cell death assays with catalytic mutant BAP1\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at target promoters with catalytic mutant and in vivo KO mouse model, single lab\",\n      \"pmids\": [\"28275095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAP1 binds YY1 transcription factor and, together with YY1, occupies the promoter regions of TRAIL death receptors DR4 and DR5 to repress their transcription; catalytically inactive BAP1 fails to reduce DR4/DR5 promoter activity, indicating deubiquitinase activity is required.\",\n      \"method\": \"Co-immunoprecipitation of BAP1-YY1, ChIP at DR4/DR5 promoters, luciferase reporter assays with wt and catalytic mutant BAP1, BAP1 and YY1 knockdown with DR4/DR5 expression readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, reporter assay with catalytic mutant, single lab\",\n      \"pmids\": [\"34597666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MBD5 and MBD6 bind to the C-terminal PHD fingers of ASXL1-3 scaffold proteins and stabilize the BAP1 complex at chromatin; depletion of MBD6 causes global loss of BAP1 chromatin occupancy and reduces BAP1-dependent gene expression and tumor growth in SCLC.\",\n      \"method\": \"Biochemical complex purification/size exclusion chromatography, mass spectrometry, ChIP-seq, RNA-seq, MBD6 depletion in SCLC cells and xenografts\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-defined interaction, ChIP-seq occupancy, and functional tumor growth readout, single lab\",\n      \"pmids\": [\"36180891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BAP1 stabilizes SMN (survival of motor neuron protein) in fibro-adipogenic progenitors (FAPs) expressing Dpp4 by preventing SMN's ubiquitination-dependent degradation; Bap1 deletion in these cells reduces SMN levels, causing neuromuscular junction degeneration and motor neuron loss, which is rescued by ubiquitination-resistant SMN (SMNK186R).\",\n      \"method\": \"Conditional Bap1 KO in Dpp4+ FAPs (mouse), ubiquitination assays, SMN protein stability assays, neuromuscular phenotype analysis, SMNK186R rescue, cell transplantation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with biochemical ubiquitination evidence and genetic rescue, single lab\",\n      \"pmids\": [\"35603786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ASXL3 functions as an adaptor protein that directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), bridging the BAP1 complex to BRD4 at active enhancers in SCLC; depletion of ASXL3 reduces genome-wide H3K27Ac levels and BRD4-dependent gene expression.\",\n      \"method\": \"Size exclusion chromatography, mass spectrometry, co-immunoprecipitation, ChIP-seq, RNA-seq, ASXL3 depletion\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-defined interaction confirmed by Co-IP and ChIP-seq, single lab\",\n      \"pmids\": [\"32669118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wild-type ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 as part of the BAP1-ASXL1 complex to regulate a subset of FOXK1/K2 target genes involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling; C-terminally truncated mutant ASXL1 loses the ability to interact with FOXK1/K2 and dominantly inhibits the wild-type ASXL1-BAP1-TF interaction.\",\n      \"method\": \"Co-immunoprecipitation, ASXL1 mutant allele deletion, rescue experiments, gene expression analysis of FOXK1/K2 target genes\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutant allele deletion rescue, single lab\",\n      \"pmids\": [\"32683582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BAP1 promotes osteoclast function via metabolic reprogramming; BAP1 deubiquitinase activity controls SLC7A11 expression through H2Aub occupancy at its promoter, which regulates cellular ROS and redirects mitochondrial metabolites away from the TCA cycle, both necessary for osteoclast cytoskeletal organization and bone resorption.\",\n      \"method\": \"Myeloid-specific Bap1 KO mice, bone mass phenotyping, H2Aub ChIP at SLC7A11 promoter, SLC7A11 expression analysis, metabolic profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mechanistic ChIP and metabolic readouts, single lab\",\n      \"pmids\": [\"37740028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BAP1 maintains chromosome stability by binding and stabilizing DIDO1 (a centrosome/spindle assembly component) through deubiquitination in renal cell carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, chromosome stability assays, expression correlation in ccRCC tissues\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and deubiquitination assay, single lab, no independent replication\",\n      \"pmids\": [\"32509391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAP1 deubiquitinates MAFF (a bZIP transcription factor) to stabilize it against K48-linked ubiquitination-mediated proteasomal degradation; stabilized MAFF upregulates DUSP5, resulting in inhibition of ERK phosphorylation and suppression of colorectal cancer growth.\",\n      \"method\": \"DUB expression library screening, co-immunoprecipitation, deubiquitination assay, DUSP5 expression analysis, ERK phosphorylation measurements, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DUB screen plus biochemical validation with downstream pathway readout, single lab\",\n      \"pmids\": [\"39151323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAP1 protects against disulfidptosis (a cell death mode caused by cystine accumulation and NADPH depletion) by repressing SLC7A11 expression via H2Aub regulation, reducing intracellular cystine uptake; overexpressing SLC7A11 or adding exogenous cystine counteracts BAP1's protective effect, and BAP1 loss also lowers NADPH levels.\",\n      \"method\": \"Cell death inhibitor profiling, disulfide bond accumulation assays, SLC7A11 KO and overexpression, cystine uptake assays, NADP+/NADPH measurements\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell death and metabolic assays with genetic rescue, single lab\",\n      \"pmids\": [\"39266549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXO3a transcriptionally regulates BAP1 by binding to the BAP1 promoter; BAP1 in turn deubiquitinates FOXO3a (at K48 sites) via its UCH domain to stabilize FOXO3a. BAP1 overexpression increases SLC7A11 repression and GPX4 suppression via H2Aub, promoting neuronal ferroptosis after subarachnoid hemorrhage.\",\n      \"method\": \"Luciferase reporter assays, co-immunoprecipitation, deubiquitination assay, ChIP at SLC7A11 promoter, BAP1 overexpression/siRNA knockdown, mouse SAH model with lentiviral shBAP1\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deubiquitination assay, promoter reporter, ChIP, and in vivo model, single lab\",\n      \"pmids\": [\"40080966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATF2 transcription factor regulates BAP1 expression by binding to the BAP1 promoter; BAP1 enhances P53 stability by reducing its proteasome-mediated degradation, and elevated P53 promotes neuronal apoptosis via the P53 pathway after subarachnoid hemorrhage.\",\n      \"method\": \"Luciferase assay (ATF2 binding to BAP1 promoter), co-immunoprecipitation, P53 ubiquitination/stability assays, BAP1 shRNA in SAH mouse model\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and promoter assay, single lab, limited mechanistic depth on BAP1-P53 deubiquitination\",\n      \"pmids\": [\"38965653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLC7A11 repression by BAP1 occurs independently of NRF2 and ATF4 transcription factors; both BAP1 (which decreases H2Aub) and PRC1 (a major H2Aub E3 ligase that increases H2Aub) repress SLC7A11 expression, suggesting dynamic regulation of H2Aub is required for SLC7A11 repression; BAP1 promotes ferroptosis induced by class I FIN (erastin) but not class II FIN (RSL3).\",\n      \"method\": \"H2Aub ChIP at SLC7A11 promoter, NRF2/ATF4 genetic knockdown, ferroptosis assays with class I and II inducers\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with genetic controls and mechanistic class-specific ferroptosis assays, extends prior work, single lab\",\n      \"pmids\": [\"30907299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Eleven high-occurrence non-catalytic mutations within BAP1's UCH domain significantly destabilize the domain, increase aggregation propensity, and cause allosteric destabilization at sites distant from the catalytic site as revealed by hydrogen-deuterium exchange mass spectrometry, providing a mechanism for how non-catalytic mutations impair BAP1 function.\",\n      \"method\": \"Multiplex spectroscopic analysis, thermodynamic assays, HDX-MS, aggregation assays for UCH domain mutants\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous biophysical and structural HDX-MS analysis with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35317997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAP1 deubiquitinase activity is required for ROS homeostasis, cell motility, and mitochondrial activity in mesothelioma cells; catalytically dead BAP1 fails to rescue these phenotypes. Monitoring intracellular ROS levels partly restores morphology and mitochondrial activity in BAP1-inactivated cells.\",\n      \"method\": \"Quantitative mass spectrometry (proteome), gene expression arrays, functional assays in BAP1-null/wt/catalytic-dead mesothelioma lines, ROS measurements\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant complementation with multiple proteomic and functional readouts, single lab\",\n      \"pmids\": [\"29069806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A BAP1 point mutation F170I (found in esophageal squamous cell carcinoma) markedly suppresses deubiquitinase and auto-deubiquitinase activity and causes cytoplasmic mislocalization of BAP1, preventing its nuclear tumor suppressor function; wild-type BAP1 induces TCEAL7 expression, which the F170I mutant cannot.\",\n      \"method\": \"Deubiquitinase activity assay of mutant vs wt BAP1, subcellular fractionation/localization studies, gene expression microarray, TCEAL7 induction assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro catalytic assay plus localization and transcriptional readout for cancer mutant, single lab\",\n      \"pmids\": [\"26081045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAP1 has a cell-intrinsic role in B lymphocyte development: Bap1 deletion in the B cell lineage causes depletion of large pre-B cells, transitional B cells, and mature B cells with broad transcriptional changes linked to cell cycle regulation, and BAP1 loss increases histone H2AK119ub levels at gene regulatory regions in pre-B cells.\",\n      \"method\": \"Conditional Bap1 KO (Bap1fl/fl mb1-Cre) mouse, flow cytometry of B cell populations, RNA-seq, ChIP-seq for BAP1 binding and H2AK119ub\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype and genome-wide mechanistic data, single lab\",\n      \"pmids\": [\"33912157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Co-occurrence of BAP1 deficiency and SF3B1 hotspot mutation induces cellular senescence and growth arrest in uveal melanoma cells, associated with downregulation of DNA-repair genes and impaired DNA damage response; this provides a mechanistic explanation for the mutual exclusivity of these mutations in uveal melanoma.\",\n      \"method\": \"Isogenic UM cell lines with BAP1 deletion and SF3B1 mutation, transcriptome analysis, DNA damage response assays, zebrafish xenograft invasion models, mouse xenograft growth assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic lines with transcriptomic and functional phenotypic readouts, single lab\",\n      \"pmids\": [\"34706158\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BAP1 is a nuclear (and partially cytoplasmic/ER-resident) deubiquitinase that removes monoubiquitin from histone H2AK119 (activated by the ASXL1/2/3 DEUBAD domain in the PR-DUB complex, as revealed by cryo-EM structure) to safeguard transcriptionally active genes from PRC1-mediated silencing; it also deubiquitinates and stabilizes multiple non-histone substrates including IP3R3 (at the ER, promoting Ca2+-driven apoptosis), HCF-1, KLF5, PTEN, LATS, HIF-1α, MCRS1, DIDO1, INO80, SMN, MAFF, and FOXO3a, and represses SLC7A11 transcription through H2Aub to promote ferroptosis; its nuclear import is mediated by transportin-1 via a PY-NLS, and IR-induced phosphorylation recruits it to DSBs to facilitate homologous recombination repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BAP1 is a UCH-family deubiquitinase that operates principally on chromatin to oppose Polycomb-mediated silencing, while also stabilizing a wide range of non-histone substrates to control cell proliferation, metabolic stress responses, and programmed cell death [#5, #7]. As the catalytic subunit of the PR-DUB/BAP1 core complex, its C-terminal extension auto-recruits it to nucleosomes and is allosterically activated by the DEUBAD domains of ASXL1/2/3 to specifically remove monoubiquitin from H2AK119, a reaction it cannot perform on DNA-damage-dependent H2A K13/K15 ubiquitination [#5]; a cryo-EM structure of the BAP1\\u2013ASXL1 DEUBAD complex on a H2AK119Ub nucleosome explains how the enzyme restructures the nucleosome to achieve this specificity and rationalizes >50 cancer-associated mutations [#6]. Rather than driving repression, the assembled BAP1 complex safeguards transcriptionally active genes against PRC1-mediated silencing [#7], with complex chromatin occupancy stabilized by MBD5/MBD6 binding to ASXL PHD fingers and bridged to active enhancers via an ASXL3\\u2013BRD4 interaction [#23, #25]. Through H2Aub regulation at the SLC7A11 promoter, BAP1 represses the cystine transporter to elevate lipid peroxidation and promote ferroptosis as a tumor-suppressor output [#0, #33]. Beyond chromatin, BAP1 deubiquitinates and stabilizes numerous substrates including HCF-1, KLF5, PTEN, LATS, HIF-1\\u03b1, and SMN, coupling its activity to cell-cycle control, Hippo and AKT signaling, hypoxic adaptation, and tissue maintenance [#3, #8, #15, #16, #17, #24]. It localizes to the ER to deubiquitinate and stabilize IP3R3, sustaining Ca2+ flux that promotes apoptosis [#1], and is required at DNA double-strand breaks, where catalytic activity and IR-induced phosphorylation drive its recruitment to facilitate BRCA1/RAD51-dependent homologous recombination [#2]. Its predominantly nuclear function depends on Transportin-1 recognition of an atypical C-terminal PY-NLS that counteracts UBE2O-mediated cytosolic retention [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing BAP1 as a deubiquitinase with a defined substrate addressed whether its growth-regulatory role was enzymatic, identifying HCF-1 as the first physiological substrate.\",\n      \"evidence\": \"MS co-purification, Co-IP, ubiquitin chain-linkage analysis, and HBM-mutant rescue\",\n      \"pmids\": [\"19815555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the chromatin/histone substrate\", \"Mechanism of growth regulation downstream of HCF-1 unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking BAP1 to DNA repair answered whether it acts in genome maintenance, showing both catalysis and IR-induced phosphorylation are needed for recruitment to double-strand breaks and homologous recombination.\",\n      \"evidence\": \"DT40 knockout, IR sensitivity, BRCA1/RAD51 foci imaging, I-SceI DSB assay, phosphomutant analysis\",\n      \"pmids\": [\"24347639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevant deubiquitination substrate at DSBs not identified\", \"Kinase responsible for IR-induced phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Multiple studies expanded the non-histone substrate repertoire and connected BAP1 loss to Polycomb mark dysregulation, defining how it controls proliferation and chromosome stability.\",\n      \"evidence\": \"Conditional Bap1 KO mice with ChIP-seq and epistasis; genome-wide DUB screens with Co-IP, deubiquitination assays, and xenograft rescue (KLF5, MCRS1)\",\n      \"pmids\": [\"26437366\", \"26419610\", \"26300492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect effects on H3K27me3/EZH2 not fully separated\", \"Whether substrate stabilization is cell-type specific unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Biochemical reconstitution defined the catalytic mechanism, showing BAP1's C-terminal extension auto-recruits it to nucleosomes and ASXL DEUBAD domains activate H2AK119-specific deubiquitination.\",\n      \"evidence\": \"In vitro reconstitution with purified nucleosomes, C-terminal mutagenesis, and substrate specificity assays (H2AK119 vs K13/15)\",\n      \"pmids\": [\"26739236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of specificity not yet resolved\", \"Role of complex on native chromatin not addressed in vitro\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying ER-localized IP3R3 deubiquitination and ER-stress transcriptional repression broadened BAP1 beyond the nucleus, linking it to Ca2+-driven apoptosis and UPR control.\",\n      \"evidence\": \"Subcellular fractionation, Co-IP, deubiquitylation and Ca2+ flux assays; ChIP at ATF3/CHOP promoters in Bap1 KO mice\",\n      \"pmids\": [\"28614305\", \"28275095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How BAP1 partitions between ER and nucleus unresolved\", \"ER targeting determinants not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Work on the SLC7A11/ferroptosis axis and additional complex interactions established a metabolic tumor-suppressor output and refined the complex's repertoire (HMGB1/HDAC1, DRED, ASXL1-MT leukemia).\",\n      \"evidence\": \"ChIP, deubiquitinase-dead mutants, cystine uptake and lipid peroxidation assays, in vivo tumor models; Co-IP and ubiquitylation assays\",\n      \"pmids\": [\"30202049\", \"34815344\", \"30463901\", \"30013160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect H2Aub effects on SLC7A11 not fully separated\", \"Tissue-specificity of complex composition unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reframing the BAP1 complex as a transcriptional activator overturned its presumed silencing role, showing it safeguards active genes against PRC1, and clarified SLC7A11 regulation requires dynamic H2Aub.\",\n      \"evidence\": \"Isogenic CRISPR lines with ChIP-seq/RNA-seq and catalytic-mutant complementation; H2Aub ChIP with NRF2/ATF4 knockdown\",\n      \"pmids\": [\"30664650\", \"30907299\", \"31657441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dynamic H2Aub turnover is coordinated with PRC1 unresolved\", \"Genome-wide rules for activation vs repression unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A series of studies defined further stabilized substrates (PTEN, LATS, HIF-1\\u03b1, INO80) and physiological roles in B-cell development and mesothelioma ROS homeostasis, mapping BAP1 onto major signaling and stress pathways.\",\n      \"evidence\": \"Co-IP, deubiquitination assays with mutagenesis, conditional KO mice, proteomics, and fork/restart assays\",\n      \"pmids\": [\"33155366\", \"31988076\", \"36656861\", \"33658435\", \"33912157\", \"29069806\", \"34597666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many substrate interactions rest on single-lab Co-IP\", \"Direct vs indirect contributions to each pathway not always separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining the PY-NLS/Transportin-1 import mechanism and chromatin-stabilizing MBD5/6 interactions explained how BAP1 reaches and persists on its nuclear targets, while HDX-MS clarified non-catalytic cancer mutations.\",\n      \"evidence\": \"Co-IP, nuclear import assays, NLS/dimerization mutagenesis; complex purification with ChIP-seq; HDX-MS on UCH-domain mutants\",\n      \"pmids\": [\"35446349\", \"36180891\", \"35317997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulation of UBE2O-driven cytosolic retention in vivo unclear\", \"Functional consequence of aggregation-prone mutants in cells not fully tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The cryo-EM structure of BAP1\\u2013ASXL1 on a H2AK119Ub nucleosome provided the atomic basis for substrate specificity and rationalized cancer mutations, completing the mechanistic picture of the chromatin reaction.\",\n      \"evidence\": \"Cryo-EM structure with biochemical deubiquitination, structure-guided mutagenesis, and cellular validation\",\n      \"pmids\": [\"37556531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures with ASXL2/ASXL3 not determined\", \"Dynamics of nucleosome restructuring not captured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recent work added regulatory feedback (FOXO3a) and disease-context outputs (disulfidptosis, neuronal ferroptosis/apoptosis), but a unified model integrating chromatin, substrate, and feedback layers is still incomplete.\",\n      \"evidence\": \"Co-IP, deubiquitination assays, promoter reporters, ChIP, and in vivo models\",\n      \"pmids\": [\"40080966\", \"39266549\", \"39151323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy among the many proposed substrates/outputs unresolved\", \"Context-dependence of pro- vs anti-death roles unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single deubiquitinase coordinately selects among its chromatin and dozens of non-histone substrates in a tissue- and context-specific manner, and how this dictates its tumor-suppressor versus cell-death outputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative substrate hierarchy\", \"Determinants of cytoplasmic vs nuclear vs ER function not integrated\", \"In vivo relevance of many single-lab substrates untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5, 8, 15, 16, 17, 24]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 7, 21, 22]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8, 15, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 18, 36]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 36]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 7, 21, 22]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 13, 30]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 8, 15, 16, 24]}\n    ],\n    \"complexes\": [\"PR-DUB / BAP1 core complex (BAP1-ASXL1/2/3)\", \"BAP1/HCF-1 complex\", \"DRED repressor complex\"],\n    \"partners\": [\"ASXL1\", \"ASXL2\", \"ASXL3\", \"HCF-1\", \"MBD6\", \"INO80\", \"IP3R3\", \"BRD4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}