{"gene":"PBRM1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2004,"finding":"BAF180 (PBRM1) is a PBAF-specific subunit required for PBAF-mediated potentiation of nuclear receptor (RXRalpha, VDR, PPARgamma) transcriptional activation in vitro; ablation in mouse embryos causes hypoplastic ventricle development and trophoblast defects. BAF180 is recruited to promoters of target genes (S100A13, RARbeta2, CRABPII) and is required for retinoic acid response.","method":"Mouse knockout (BAF180 ablation), embryonic aggregation analysis, in vitro transcriptional activation assay, chromatin immunoprecipitation (ChIP)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vitro assay, KO mouse with defined phenotype, ChIP confirming promoter recruitment, multiple orthogonal methods","pmids":["15601824"],"is_preprint":false},{"year":2008,"finding":"BAF180 (PBRM1) is required for epicardial epithelial-to-mesenchymal transition (EMT) and coronary vessel development; BAF180 mutant epicardial cells show compromised migration and EMT potentials, and expression of FGF, TGF, and VEGF pathway genes is downregulated in mutant hearts.","method":"BAF180 knockout mouse model, 3D collagen gel migration/EMT assay, PECAM and alpha-SMA staining, quantitative RT-PCR","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined cellular phenotype, multiple functional assays (migration, immunostaining, qRT-PCR)","pmids":["18508041"],"is_preprint":false},{"year":2008,"finding":"BAF180 (PBRM1) is required for proper p21/WAF1/CIP1 expression and G1 arrest; endogenous BAF180 binds to the p21 promoter and is required for p21 induction by TGF-beta and gamma-radiation. BAF180 complementation of BAF180-mutant tumor cells causes G1 arrest dependent on p21 upregulation.","method":"Cell complementation of BAF180-mutant tumor cells, chromatin immunoprecipitation (ChIP) at p21 promoter, TGF-beta/gamma-radiation treatment, cell cycle analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct promoter binding, functional rescue by complementation, multiple stimuli tested","pmids":["18339845"],"is_preprint":false},{"year":2010,"finding":"BAF180 (PBRM1) regulates p53 transcriptional activity toward a subset of p53 target genes required for replicative and oncogenic stress senescence induction. Loss of BAF180 impairs replicative senescence in primary human cells.","method":"Loss-of-function genetic screen in primary human cells, p53 transcriptional activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen with defined phenotypic readout, single lab","pmids":["20660729"],"is_preprint":false},{"year":2012,"finding":"BAF180 (PBRM1) is required for centromeric cohesion in mouse and human cells. Cancer-associated BAF180 mutations fail to support cohesion, and BAF180 loss leads to dynamic chromosome instability following DNA damage.","method":"BAF180 depletion in mouse and human cells, cohesion assay, chromosome instability analysis, functional testing of tumor-derived mutants in yeast cohesion assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, tumor-derived mutants functionally tested, conservation confirmed in yeast","pmids":["24613357"],"is_preprint":false},{"year":2012,"finding":"BAF180 (PBRM1) directly binds regulatory elements in the IL-10 locus and represses IL-10 transcription in Th2 cells. In the absence of BAF180, BAF250-containing BAF complexes replace it at the IL-10 locus, resulting in increased histone acetylation and CBP recruitment.","method":"BAF180-deficient mouse T cells, ChIP at IL-10 locus, histone acetylation assay, CBP recruitment analysis","journal":"BMC immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct locus binding, mechanistic follow-up with histone modifications and CBP recruitment, KO mouse model","pmids":["22336179"],"is_preprint":false},{"year":2015,"finding":"BAH domains of BAF180 (PBRM1) are required for PCNA ubiquitination during S-phase after UV irradiation; the BAH domain region promotes PCNA ubiquitination independent of PBAF complex assembly and ATPase activity.","method":"Expression of BAF180 deletion mutants in cells, ubiquitinated PCNA western blot, UV irradiation assay, PBAF assembly analysis","journal":"Mutation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion analysis, functional readout (PCNA ubiquitination), single lab","pmids":["26117423"],"is_preprint":false},{"year":2016,"finding":"BAF180 (PBRM1) deletion in primary mouse embryonic fibroblasts triggers cell cycle arrest and premature cellular senescence through elevated p21 expression. BAF180 binds the p21 promoter and suppresses its transcription; BAF180 deletion enhances binding of activation-associated histone modifications to the p21 promoter. Deletion of p21 rescues senescence in BAF180-deficient MEFs.","method":"Conditional somatic knockout in mice, ChIP at p21 promoter, histone modification analysis, p21 genetic rescue experiment, hematopoietic stem cell functional assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse, ChIP, genetic epistasis (p21 rescue), multiple orthogonal readouts","pmids":["26992241"],"is_preprint":false},{"year":2017,"finding":"PBRM1 loss amplifies HIF1 and STAT3 transcriptional outputs driven by VHL deficiency. Combined kidney-specific deletion of Vhl and Pbrm1 (but not either alone) results in multifocal, transplantable clear cell kidney cancers in mice, with convergence on mTOR activation as a third driver event.","method":"Kidney-specific conditional knockout of Vhl and Pbrm1 in mice, transcriptional analysis, mTOR pathway analysis, tumor transplantation assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in conditional KO mouse model, multiple orthogonal methods, functional transplantation confirmation","pmids":["28329682"],"is_preprint":false},{"year":2017,"finding":"PBRM1 inactivation amplifies the HIF transcriptional signature in VHL-null ccRCC. BAF180 growth suppression requires formation of a canonical PBAF complex containing BRG1; a tumor-associated BAF180 mutant fails to form this complex and does not suppress growth.","method":"ccRCC cell line proliferation assays in vitro and in vivo xenograft, biochemical PBAF complex assembly assay, HIF transcriptional signature analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional in vitro and in vivo assays, biochemical complex assembly, tumor mutant analysis","pmids":["28082722"],"is_preprint":false},{"year":2017,"finding":"Bap1 and Pbrm1 loss (with Vhl) in PAX8-expressing cells drives ccRCC of different grades in mice; Bap1-deficient tumors are high grade with greater mTORC1 activation than Pbrm1-deficient tumors. Disrupting one Tsc1 allele in Pbrm1-deficient kidneys triggers higher grade ccRCC, implicating mTORC1 as a grade rheostat.","method":"Conditional KO mouse models with multiple Cre drivers, histological grading, mTORC1 pathway analysis, genetic epistasis (Tsc1 heterozygous deletion)","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models, genetic epistasis with Tsc1, defined histological phenotype","pmids":["28473526"],"is_preprint":false},{"year":2017,"finding":"Loss of VHL alone causes DNA replication stress and damage accumulation that constrains cellular growth; concomitant PBRM1 loss rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation. Combined Vhl/Pbrm1 deletion in mouse kidney is sufficient for fully-penetrant multifocal carcinomas.","method":"VHL/PBRM1 co-deletion in cells and conditional KO mouse, DNA replication stress assays (DNA damage markers), proliferation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis, functional replication stress assay, KO mouse model with defined phenotype","pmids":["29229903"],"is_preprint":false},{"year":2017,"finding":"Drosophila Bap180 (ortholog of PBRM1/BAF180) is induced by IMD-Relish signaling in the gut and feeds back to restrain overreactive IMD signaling and repress TNF/eiger expression, maintaining intestinal innate immune homeostasis. Intestinal Baf180 targeting in mice increases susceptibility to Citrobacter rodentium infection.","method":"Drosophila intestinal Bap180 knockdown/overexpression, infection models, genetic epistasis with IMD pathway, mouse intestinal Baf180 targeting","journal":"Nature microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila genetic epistasis with defined immune phenotype, conservation in mouse model, single lab","pmids":["28418397"],"is_preprint":false},{"year":2018,"finding":"PBRM1 bromodomains BD2 and BD4 mediate binding to acetylated histone peptides and modified nucleosomes. BD1 and BD5 enhance nucleosome interactions of BD2 and BD4 respectively, while BD3 attenuates them. Binding-pocket missense mutations in BD4 (but not BD2) found in ccRCC disrupt PBRM1-chromatin interactions and accelerate ccRCC cell proliferation.","method":"Histone microarrays, nucleosome binding assays with recombinant and cellular nucleosomes, BD missense mutant analysis, ccRCC cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with histone microarrays and nucleosomes, mutagenesis, functional cellular readout","pmids":["29986887"],"is_preprint":false},{"year":2019,"finding":"PBRM1 acts as a reader of p53 acetylation at lysine 382 (K382Ac) through its bromodomain 4 (BD4). Mutations on key BD4 residues disrupt recognition of p53 K382Ac, reduce p53 binding to target promoters (including CDKN1A/p21), impair p53 transcriptional activity, and abolish PBRM1 tumor suppressor function in kidney cancer xenografts.","method":"Biochemical binding assay (PBRM1 BD4 with K382Ac p53 peptide), ChIP at CDKN1A promoter, BD4 mutagenesis, p53 transcriptional reporter, xenograft tumor suppression assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical binding, mutagenesis, ChIP, functional xenograft, multiple orthogonal methods in one study","pmids":["31863007"],"is_preprint":false},{"year":2019,"finding":"Full-length PBRM1 (but not individual bromodomains) strongly binds H3K14ac; BDs 2, 4, and 5 collaborate for high-affinity H3K14ac binding. Simultaneous point mutations in BDs 2, 4, and 5 prevent H3K14ac recognition, alter promoter binding, change gene expression, and cause PBRM1 to relocalize to the cytoplasm. Tumor-derived BD2 mutations alone weaken H3K14ac binding and abolish tumor suppressor activity in xenografts.","method":"Purified BD protein binding assays (quantitative), full-length PBRM1 H3K14ac binding assay, BD mutagenesis, ChIP, transcriptional profiling, xenograft tumor suppression, subcellular localization by imaging","journal":"Molecular oncology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with purified proteins, mutagenesis, ChIP, localization, xenograft, multiple orthogonal methods","pmids":["30585695"],"is_preprint":false},{"year":2020,"finding":"PBRM1/Pbrm1 deficiency reduces binding of BRG1 to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and subsequent expression of IFNγ target genes, leading to a less immunogenic tumor microenvironment.","method":"ChIP (BRG1 at Ifngr2 promoter), STAT1 phosphorylation assay, PBRM1-deficient cell lines and murine models, patient cohort analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct promoter binding, STAT1 phosphorylation as mechanistic readout, in vitro and in vivo models","pmids":["32358509"],"is_preprint":false},{"year":2020,"finding":"BMPs and osteogenic signals in mesenchymal stromal cells selectively induce PBAF components Pbrm1, Arid2, and Brd7. Pbrm1/PBAF deficiency impairs Smad1/5/8 activation through locus-specific epigenomic remodeling involving Pbrm1 bromodomains, and transcriptionally downregulates Bmpr/TgfβrII expression. Gain of function of BmprIβ/TgfβrII in PBAF-deficient MSCs partly restores osteogenesis.","method":"Conditional Pbrm1 loss in MSCs, ATAC-seq/ChIP-seq (bromodomain-specific), Smad1/5/8 activation assay, BmprIβ/TgfβrII rescue experiment, in vivo ossification assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — locus-specific chromatin analysis, Smad activation assay, genetic rescue, single lab","pmids":["32348751"],"is_preprint":false},{"year":2021,"finding":"PBRM1 deficiency causes elevated replication stress, micronuclei, and R-loops in cells; multiple R-loop processing factors are downregulated in PBRM1-defective tumor cells. PARP and ATR inhibitors are synthetic lethal with PBRM1 deficiency, and exogenous RNase H1 expression reverses PARP inhibitor sensitivity in PBRM1-deficient cells, implicating R-loop accumulation as a mechanistic basis.","method":"Functional genomic screens, R-loop quantification, replication stress markers, quantitative mass spectrometry of R-loop factors, RNase H1 rescue experiment, xenograft model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal functional screens, MS proteomics, genetic rescue (RNase H1), in vitro and in vivo models","pmids":["33888468"],"is_preprint":false},{"year":2021,"finding":"PAX8 (master proximal tubule transcription factor) recruits PBRM1/PBAF specifically (not BAF) as a coactivator. In RCC cells lacking PBRM1, corepressors dominate the PAX8 hub, repressing key PAX8 target genes with loss of H3K27 acetylation. Re-introduction of PBRM1, or depletion of opposing corepressors, restores PAX8 target gene expression and induces terminal epithelial differentiation.","method":"Unbiased proteomics (PAX8 interactome), reciprocal Co-IP (PAX8-PBRM1/PBAF), ChIP (H3K27ac, H3K4me3), PBRM1 re-expression, siRNA corepressor depletion, terminal differentiation assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, MS proteomics, ChIP, functional rescue, multiple orthogonal methods","pmids":["34551289"],"is_preprint":false},{"year":2021,"finding":"PBRM1 cooperates with YTHDF2 (an m6A reader) to control HIF-1α protein translation; PBRM1 (but not BRG1) interacts with YTHDF2, and HIF-1α mRNA is m6A-modified and bound by both PBRM1 and YTHDF2. PBRM1 is required for YTHDF2 binding to HIF-1α mRNA. This represents a SWI/SNF-independent function for PBRM1.","method":"Co-IP (PBRM1-YTHDF2 interaction), RNA immunoprecipitation (HIF-1α mRNA), polysome/translation assay, PBRM1 KD with HIF-1α protein/mRNA analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, RNA-IP, translation assay, single lab with single mechanistic paper","pmids":["34200988"],"is_preprint":false},{"year":2022,"finding":"PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci (distal enhancers with NF-κB motifs), activating the pro-tumorigenic NF-κB pathway. PBRM1-deficient PBAF retains SMARCA4-ARID2 association but has loosely tethered BRD7. SMARCA4 ATPase activity maintains chromatin occupancy of RELA at newly acquired sites, and proteasome inhibitor bortezomib suppresses RELA occupancy and delays PBRM1-deficient tumor growth.","method":"ChIP-seq (PBAF subunit redistribution), Co-IP (PBAF complex composition), SMARCA4 ATPase mutant analysis, RELA ChIP, bortezomib treatment in vivo xenograft","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq genome-wide, Co-IP complex composition, ATPase mutant, in vivo therapeutic experiment, multiple orthogonal methods","pmids":["37095322"],"is_preprint":false},{"year":2022,"finding":"PBRM1 is degraded via proteasomal degradation induced by p53 activation. p53-dependent PBRM1 regulation is post-translational (not transcriptional), as demonstrated by pulse-chase experiments and proteasome inhibitor rescue.","method":"siRNA knockdown of p53, pulse-chase experiment, proteasome inhibitor treatment, RCC cell lines and ex vivo tissue","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulse-chase establishing post-translational mechanism, proteasome inhibitor rescue, siRNA validation; single lab","pmids":["26178300"],"is_preprint":false},{"year":2022,"finding":"UBE3A (an E3 ubiquitin ligase) binds PBRM1 and regulates its stability via ubiquitin-mediated proteasomal degradation. RBPJ/DAPK3 modulates UBE3A E3 ligase activity by interfering with PKA phosphorylation of UBE3A. The RBPJ/DAPK3/UBE3A axis controls PBRM1 protein levels and downstream p21 expression, affecting RCC sensitivity to CDK4/6 inhibitors.","method":"Unbiased mass spectrometry of PBRM1 interactome, Co-IP (PBRM1-UBE3A), ubiquitination assay, PKA phosphorylation of UBE3A, PBRM1 stability assay, CDK4/6 inhibitor sensitivity assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction, Co-IP, ubiquitination assay, functional drug sensitivity readout; single lab","pmids":["35368029"],"is_preprint":false},{"year":2022,"finding":"PBRM1 inactivation upregulates human endogenous retroviruses (hERVs) in a HIF1α- and HIF2α-dependent manner in ccRCC, as confirmed by in vitro PBRM1, HIF1A, and HIF2A silencing followed by RNA sequencing.","method":"RNA sequencing after siRNA knockdown of PBRM1/HIF1A/HIF2A, TCGA and IMmotion150 cohort analysis","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with genetic perturbation, mechanistic epistasis via HIF knockdown, single lab","pmids":["35013001"],"is_preprint":false},{"year":2023,"finding":"MUC1-C is necessary for PBRM1 expression and forms a nuclear complex with PBRM1 in triple-negative breast cancer cells. MUC1-C and PBRM1 cooperatively drive STAT1 and IRF1 expression by increasing chromatin accessibility at their gene promoters (shown by RNA-seq and ATAC-seq), promoting chronic IFN pathway activation and DNA damage resistance.","method":"Co-IP (MUC1-C/PBRM1 nuclear complex), RNA-seq, ATAC-seq, MUC1-C knockdown, PBRM1 dependency analysis, DNA damage assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ATAC-seq, RNA-seq with KD, multiple readouts; single lab","pmids":["36445328"],"is_preprint":false},{"year":2023,"finding":"PBRM1 bromodomains BD2 and BD4 bind double-stranded RNA elements in addition to acetylated histones. Disruption of the RNA-binding pocket compromises PBRM1 chromatin binding and inhibits PBRM1-mediated cellular growth suppression effects.","method":"In vitro RNA binding assays (BD2, BD4), RNA-binding pocket mutagenesis, chromatin binding assay, cellular growth assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical RNA binding assay, mutagenesis of binding pocket, functional cellular readout; single lab","pmids":["36808431"],"is_preprint":false},{"year":2020,"finding":"PBRM1 loss in tumor cells causes resistance to MHC-unrestricted cytotoxic lymphocyte (NK cell) killing in genome-wide genetic screens. PBRM1 and the GPI biosynthetic pathway regulate NK cell receptor ligands on tumor cells and promote cytolytic granule secretion in cytotoxic lymphocytes.","method":"Genome-wide CRISPR/genetic screen, NK cell killing assay, NK cell receptor ligand expression analysis, cytolytic granule secretion assay","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen, functional NK killing assay, ligand expression analysis; single study","pmids":["33246952"],"is_preprint":false}],"current_model":"PBRM1/BAF180 is the chromatin-targeting subunit of the PBAF SWI/SNF complex, tethering PBAF to chromatin through cooperative bromodomain-mediated recognition of acetylated histones (H3K14ac via BDs 2/4/5, and p53-K382Ac via BD4), thereby regulating transcription of genes involved in p21/cell cycle control, HIF-target gene expression, NF-κB signaling, IFN-γ/STAT1 signaling, and cellular differentiation; PBRM1 loss leads to ectopic PBAF redistribution to NF-κB enhancers, amplified HIF transcriptional output, replication stress and R-loop accumulation, impaired cohesion and genome stability, and altered tumor immune recognition—while PBRM1 protein stability is itself regulated by p53-induced UBE3A-mediated proteasomal degradation and by a novel SWI/SNF-independent interaction with YTHDF2 to facilitate HIF-1α mRNA translation."},"narrative":{"mechanistic_narrative":"PBRM1/BAF180 is the chromatin-targeting subunit of the PBAF SWI/SNF chromatin-remodeling complex, controlling transcriptional programs that govern cell-cycle arrest, cellular differentiation, genome stability, and immune recognition [PMID:15601824, PMID:18339845, PMID:34551289]. It tethers PBAF to chromatin through cooperative bromodomain recognition of acetylated histones: full-length PBRM1 binds H3K14ac via the collaborative action of bromodomains BD2, BD4 and BD5, and tumor-derived bromodomain mutations weaken this interaction, mislocalize PBRM1, and abolish its tumor-suppressor activity [PMID:29986887, PMID:30585695]. The same bromodomains read additional acetyl marks and nucleic acids—BD4 recognizes p53 acetylated at K382 to promote p53 binding at target promoters including CDKN1A/p21, and BD2/BD4 also bind double-stranded RNA elements required for chromatin engagement [PMID:31863007, PMID:36808431]. Through these targeting activities PBRM1 binds the p21 promoter to enforce p21-dependent G1 arrest and senescence, supports centromeric cohesion, and restrains replication stress and R-loop accumulation [PMID:18339845, PMID:24613357, PMID:26992241, PMID:33888468]. In clear cell renal carcinoma, combined PBRM1 and VHL loss amplifies HIF and STAT3 transcriptional output, relieves VHL-induced replication stress, and drives tumorigenesis with convergence on mTORC1 [PMID:28329682, PMID:28082722, PMID:29229903, PMID:28473526]. PBRM1 loss also causes ectopic PBAF redistribution to NF-κB enhancers and reduces BRG1 occupancy at the IFNγ receptor promoter, shaping a less immunogenic tumor microenvironment [PMID:37095322, PMID:32358509]. Beyond its remodeling role, PBRM1 has a SWI/SNF-independent function cooperating with the m6A reader YTHDF2 to control HIF-1α mRNA translation, and its protein stability is governed by p53-induced, UBE3A-mediated proteasomal degradation [PMID:34200988, PMID:26178300, PMID:35368029].","teleology":[{"year":2004,"claim":"Established PBRM1 as the defining PBAF-specific subunit and a chromatin-recruited transcriptional coactivator, framing all later mechanistic work.","evidence":"Mouse knockout, in vitro nuclear-receptor transcription assay, and ChIP at target promoters","pmids":["15601824"],"confidence":"High","gaps":["Molecular basis of promoter targeting not defined","Did not address tumor-suppressor function"]},{"year":2008,"claim":"Showed PBRM1 controls developmental cell behaviors and links it to p21-dependent cell-cycle arrest, revealing both differentiation and growth-control roles.","evidence":"Knockout mouse epicardial EMT/migration assays and ChIP-coupled p21 induction in complemented tumor cells","pmids":["18508041","18339845"],"confidence":"High","gaps":["Mechanism by which PBRM1 represses vs. activates p21 across contexts unresolved","Direct chromatin-reading determinants not yet mapped"]},{"year":2010,"claim":"Connected PBRM1 to p53-dependent senescence, positioning it within stress-response transcriptional control.","evidence":"Loss-of-function screen in primary human cells with p53 transcriptional readouts","pmids":["20660729"],"confidence":"Medium","gaps":["Which p53 targets are PBRM1-dependent not fully defined","Single-lab functional screen"]},{"year":2012,"claim":"Identified non-transcriptional and lineage-specific roles—centromeric cohesion/genome stability and direct repression of the IL-10 locus in Th2 cells, with subunit competition by BAF250.","evidence":"Cohesion and chromosome-instability assays with tumor-mutant testing; ChIP and histone-acetylation/CBP analysis in KO T cells","pmids":["24613357","22336179"],"confidence":"High","gaps":["Mechanism linking PBRM1 to cohesin loading unknown","Generality of BAF/PBAF subunit swapping across loci untested"]},{"year":2016,"claim":"Reinforced the p21 axis using conditional knockout and genetic epistasis, showing PBRM1 loss causes premature senescence rescuable by p21 deletion.","evidence":"Conditional mouse KO, ChIP, histone-modification analysis, and p21 genetic rescue","pmids":["26992241"],"confidence":"High","gaps":["How PBRM1 toggles between p21 repression and induction unresolved"]},{"year":2017,"claim":"Defined PBRM1 as a renal tumor suppressor whose loss with VHL drives ccRCC by amplifying HIF/STAT3 output, relieving replication stress, and converging on mTORC1, and showed growth suppression requires intact PBAF assembly.","evidence":"Kidney-specific Vhl/Pbrm1 conditional KO mice, biochemical PBAF assembly assays, replication-stress markers, and mTORC1/Tsc1 epistasis","pmids":["28329682","28082722","29229903","28473526"],"confidence":"High","gaps":["Direct chromatin targets mediating HIF amplification not enumerated","Mechanism of replication-stress rescue at the molecular level incomplete"]},{"year":2017,"claim":"Extended PBRM1 function to innate immune homeostasis and BAH-domain-dependent PCNA ubiquitination, showing complex- and domain-specific activities.","evidence":"Drosophila IMD-pathway epistasis with mouse infection model; BAF180 deletion-mutant PCNA-ubiquitination assays after UV","pmids":["28418397","26117423"],"confidence":"Medium","gaps":["BAH-domain mechanism of promoting PCNA ubiquitination undefined","Single-lab domain-deletion analyses"]},{"year":2019,"claim":"Resolved the molecular logic of PBRM1 chromatin targeting: multivalent bromodomain reading of H3K14ac and p53-K382Ac, with tumor mutations disrupting binding and tumor suppression.","evidence":"Purified bromodomain and full-length binding assays, histone microarrays, BD mutagenesis, ChIP, transcriptional profiling, and xenografts","pmids":["29986887","30585695","31863007"],"confidence":"High","gaps":["Structural basis of inter-bromodomain cooperativity not solved","Full acetyl-mark repertoire incompletely mapped"]},{"year":2020,"claim":"Linked PBRM1 to tumor immune recognition through both IFNγ/STAT1 signaling and NK-cell-mediated killing, establishing an immunological dimension to its loss.","evidence":"ChIP of BRG1 at Ifngr2, STAT1 phosphorylation assays, and genome-wide CRISPR NK-killing screens with ligand/granule readouts","pmids":["32358509","33246952"],"confidence":"Medium","gaps":["Causal chain from chromatin to NK ligand expression incomplete","Single-study findings for each axis"]},{"year":2021,"claim":"Defined PBRM1 as a guardian against replication stress/R-loops and a context-specific PAX8 coactivator, while revealing a SWI/SNF-independent translational role via YTHDF2.","evidence":"Functional genomic screens with RNase H1 rescue and synthetic-lethality assays; PAX8 interactome proteomics with reciprocal Co-IP and ChIP; PBRM1-YTHDF2 Co-IP/RNA-IP and translation assays","pmids":["33888468","34551289","34200988"],"confidence":"High","gaps":["Which R-loop processing factors are direct PBRM1 transcriptional targets unclear","YTHDF2 cooperation rests on single-lab Co-IP/RNA-IP"]},{"year":2022,"claim":"Showed PBRM1 loss produces gain-of-function via ectopic PBAF redistribution to NF-κB enhancers and defined how PBRM1 protein levels are controlled by p53-induced UBE3A-mediated degradation.","evidence":"ChIP-seq of PBAF subunit redistribution with SMARCA4 ATPase mutants and bortezomib xenografts; pulse-chase, proteasome-inhibitor rescue, and PBRM1-UBE3A interactome/ubiquitination assays","pmids":["37095322","26178300","35368029","35013001"],"confidence":"High","gaps":["Determinants directing ectopic PBAF to NF-κB motifs unresolved","Upstream signals coupling p53 to UBE3A-PBRM1 turnover incompletely defined"]},{"year":2023,"claim":"Broadened PBRM1's binding repertoire to double-stranded RNA and identified a MUC1-C partnership driving IFN-pathway transcription in breast cancer, indicating roles beyond renal cancer.","evidence":"In vitro RNA-binding and binding-pocket mutagenesis with chromatin/growth readouts; MUC1-C/PBRM1 Co-IP with RNA-seq and ATAC-seq","pmids":["36808431","36445328"],"confidence":"Medium","gaps":["Functional role of RNA binding in chromatin targeting vs. other processes unclear","MUC1-C cooperation from a single lab"]},{"year":null,"claim":"How PBRM1's distinct activities—bromodomain acetyl/RNA reading, PBAF tethering, SWI/SNF-independent translation, and protein turnover—are integrated to specify locus selection and context-dependent tumor suppression versus gain-of-function remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length PBRM1 engaging the nucleosome","Mechanism directing ectopic PBAF to oncogenic enhancers unknown","Integration of chromatin and RNA/translational functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[13,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,14,19]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[26,20]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,15,25]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[2,21]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,15,21]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,19]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,9,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,27,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18,6]}],"complexes":["PBAF SWI/SNF complex"],"partners":["SMARCA4","ARID2","BRD7","TP53","YTHDF2","UBE3A","PAX8","MUC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86U86","full_name":"Protein polybromo-1","aliases":["BRG1-associated factor 180","BAF180","Polybromo-1D"],"length_aa":1689,"mass_kda":192.9,"function":"Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Required for the stability of the SWI/SNF chromatin remodeling complex SWI/SNF-B (PBAF). Acts as a negative regulator of cell proliferation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q86U86/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PBRM1","classification":"Not Classified","n_dependent_lines":116,"n_total_lines":1208,"dependency_fraction":0.09602649006622517},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PHF10","stoichiometry":10.0},{"gene":"NUCKS1","stoichiometry":4.0},{"gene":"SMARCA4","stoichiometry":4.0},{"gene":"H1F0","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PBRM1","total_profiled":1310},"omim":[{"mim_id":"615619","title":"CHOLANGIOCARCINOMA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/615619"},{"mim_id":"609837","title":"SMALL NUCLEOLAR RNA, C/D BOX, 115-1; SNORD115-1","url":"https://www.omim.org/entry/609837"},{"mim_id":"606083","title":"POLYBROMO 1; PBRM1","url":"https://www.omim.org/entry/606083"},{"mim_id":"603089","title":"BRCA1-ASSOCIATED PROTEIN 1; BAP1","url":"https://www.omim.org/entry/603089"},{"mim_id":"603024","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 1A; ARID1A","url":"https://www.omim.org/entry/603024"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PBRM1"},"hgnc":{"alias_symbol":["BAF180","PB1","SMARCH1"],"prev_symbol":[]},"alphafold":{"accession":"Q86U86","domains":[{"cath_id":"1.20.920.10","chopping":"44-154","consensus_level":"medium","plddt":88.7368,"start":44,"end":154},{"cath_id":"1.20.920.10","chopping":"197-294","consensus_level":"medium","plddt":89.6798,"start":197,"end":294},{"cath_id":"1.20.920.10","chopping":"386-491","consensus_level":"high","plddt":89.3726,"start":386,"end":491},{"cath_id":"1.20.920.10","chopping":"534-626","consensus_level":"high","plddt":91.1088,"start":534,"end":626},{"cath_id":"1.20.920.10","chopping":"668-765","consensus_level":"high","plddt":90.0787,"start":668,"end":765},{"cath_id":"1.20.920.10","chopping":"775-920","consensus_level":"high","plddt":91.5519,"start":775,"end":920},{"cath_id":"2.30.30.490","chopping":"947-1103","consensus_level":"high","plddt":87.948,"start":947,"end":1103},{"cath_id":"2.30.30.490","chopping":"1135-1312","consensus_level":"high","plddt":89.9426,"start":1135,"end":1312},{"cath_id":"1.10.30.10","chopping":"1386-1438","consensus_level":"medium","plddt":87.1975,"start":1386,"end":1438}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86U86","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86U86-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86U86-F1-predicted_aligned_error_v6.png","plddt_mean":72.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PBRM1","jax_strain_url":"https://www.jax.org/strain/search?query=PBRM1"},"sequence":{"accession":"Q86U86","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86U86.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86U86/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86U86"}},"corpus_meta":[{"pmid":"21248752","id":"PMC_21248752","title":"Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21248752","citation_count":1011,"is_preprint":false},{"pmid":"23333114","id":"PMC_23333114","title":"Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.","date":"2013","source":"The Lancet. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23333114","citation_count":377,"is_preprint":false},{"pmid":"16201016","id":"PMC_16201016","title":"Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1.","date":"2005","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/16201016","citation_count":296,"is_preprint":false},{"pmid":"25140902","id":"PMC_25140902","title":"Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25140902","citation_count":200,"is_preprint":false},{"pmid":"28329682","id":"PMC_28329682","title":"The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28329682","citation_count":170,"is_preprint":false},{"pmid":"25604444","id":"PMC_25604444","title":"The PB1 domain in auxin response factor and Aux/IAA proteins: a versatile protein interaction module in the auxin response.","date":"2015","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/25604444","citation_count":163,"is_preprint":false},{"pmid":"32013669","id":"PMC_32013669","title":"Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/32013669","citation_count":162,"is_preprint":false},{"pmid":"16949360","id":"PMC_16949360","title":"Cell signaling and function organized by PB1 domain interactions.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16949360","citation_count":162,"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":"15601824","id":"PMC_15601824","title":"Polybromo protein BAF180 functions in mammalian cardiac chamber maturation.","date":"2004","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/15601824","citation_count":147,"is_preprint":false},{"pmid":"32358509","id":"PMC_32358509","title":"PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32358509","citation_count":147,"is_preprint":false},{"pmid":"20660729","id":"PMC_20660729","title":"Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20660729","citation_count":147,"is_preprint":false},{"pmid":"11483497","id":"PMC_11483497","title":"Novel modular domain PB1 recognizes PC motif to mediate functional protein-protein interactions.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11483497","citation_count":141,"is_preprint":false},{"pmid":"26057645","id":"PMC_26057645","title":"TRIM32 Senses and Restricts Influenza A Virus by Ubiquitination of PB1 Polymerase.","date":"2015","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/26057645","citation_count":140,"is_preprint":false},{"pmid":"18339845","id":"PMC_18339845","title":"BAF180 is a critical regulator of p21 induction and a tumor suppressor mutated in breast cancer.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18339845","citation_count":135,"is_preprint":false},{"pmid":"17726178","id":"PMC_17726178","title":"Structure and function of the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants.","date":"2007","source":"Science's STKE : signal transduction knowledge environment","url":"https://pubmed.ncbi.nlm.nih.gov/17726178","citation_count":127,"is_preprint":false},{"pmid":"28082722","id":"PMC_28082722","title":"Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL-/- clear cell renal carcinoma.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28082722","citation_count":125,"is_preprint":false},{"pmid":"33577621","id":"PMC_33577621","title":"The PB1 protein of influenza A virus inhibits the innate immune response by targeting MAVS for NBR1-mediated selective autophagic degradation.","date":"2021","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/33577621","citation_count":122,"is_preprint":false},{"pmid":"22949125","id":"PMC_22949125","title":"Loss of PBRM1 expression is associated with renal cell carcinoma progression.","date":"2012","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22949125","citation_count":122,"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":"24166983","id":"PMC_24166983","title":"Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma.","date":"2013","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24166983","citation_count":113,"is_preprint":false},{"pmid":"33888468","id":"PMC_33888468","title":"PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33888468","citation_count":101,"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":"16861740","id":"PMC_16861740","title":"Aurothiomalate inhibits transformed growth by targeting the PB1 domain of protein kinase Ciota.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16861740","citation_count":92,"is_preprint":false},{"pmid":"26166446","id":"PMC_26166446","title":"BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies.","date":"2015","source":"Expert review of molecular diagnostics","url":"https://pubmed.ncbi.nlm.nih.gov/26166446","citation_count":90,"is_preprint":false},{"pmid":"24613357","id":"PMC_24613357","title":"BAF180 promotes cohesion and prevents genome instability and aneuploidy.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24613357","citation_count":86,"is_preprint":false},{"pmid":"30601030","id":"PMC_30601030","title":"Radiogenomics in Clear Cell Renal Cell Carcinoma: Machine Learning-Based High-Dimensional Quantitative CT Texture Analysis in Predicting PBRM1 Mutation Status.","date":"2019","source":"AJR. American journal of roentgenology","url":"https://pubmed.ncbi.nlm.nih.gov/30601030","citation_count":86,"is_preprint":false},{"pmid":"29229903","id":"PMC_29229903","title":"Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29229903","citation_count":85,"is_preprint":false},{"pmid":"20844191","id":"PMC_20844191","title":"Influenza A virus protein PB1-F2 exacerbates IFN-beta expression of human respiratory epithelial cells.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20844191","citation_count":84,"is_preprint":false},{"pmid":"27100670","id":"PMC_27100670","title":"PBRM1 Regulates the Expression of Genes Involved in Metabolism and Cell Adhesion in Renal Clear Cell Carcinoma.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27100670","citation_count":81,"is_preprint":false},{"pmid":"20953627","id":"PMC_20953627","title":"Current knowledge on PB1-F2 of influenza A viruses.","date":"2010","source":"Medical microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20953627","citation_count":75,"is_preprint":false},{"pmid":"19713972","id":"PMC_19713972","title":"Of the atypical PKCs, Par-4 and p62: recent understandings of the biology and pathology of a PB1-dominated complex.","date":"2009","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/19713972","citation_count":66,"is_preprint":false},{"pmid":"31863007","id":"PMC_31863007","title":"PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31863007","citation_count":65,"is_preprint":false},{"pmid":"18508041","id":"PMC_18508041","title":"Coronary development is regulated by ATP-dependent SWI/SNF chromatin remodeling component BAF180.","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18508041","citation_count":65,"is_preprint":false},{"pmid":"17224071","id":"PMC_17224071","title":"The PB1-F2 protein of Influenza A virus: increasing pathogenicity by disrupting alveolar macrophages.","date":"2007","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/17224071","citation_count":62,"is_preprint":false},{"pmid":"24063284","id":"PMC_24063284","title":"Enhancement of proliferation and invasion by MicroRNA-590-5p via targeting PBRM1 in clear cell renal carcinoma cells.","date":"2013","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/24063284","citation_count":61,"is_preprint":false},{"pmid":"30660076","id":"PMC_30660076","title":"Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma.","date":"2019","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30660076","citation_count":57,"is_preprint":false},{"pmid":"17052982","id":"PMC_17052982","title":"Structural characterization and oligomerization of PB1-F2, a proapoptotic influenza A virus protein.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17052982","citation_count":57,"is_preprint":false},{"pmid":"26992241","id":"PMC_26992241","title":"BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26992241","citation_count":56,"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":"8645093","id":"PMC_8645093","title":"Influenza virus PB1 protein is the minimal and essential subunit of RNA polymerase.","date":"1996","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8645093","citation_count":55,"is_preprint":false},{"pmid":"29286299","id":"PMC_29286299","title":"Evolution and Virulence of Influenza A Virus Protein PB1-F2.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29286299","citation_count":54,"is_preprint":false},{"pmid":"26601953","id":"PMC_26601953","title":"Amyloid Assemblies of Influenza A Virus PB1-F2 Protein Damage Membrane and Induce Cytotoxicity.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26601953","citation_count":50,"is_preprint":false},{"pmid":"27046062","id":"PMC_27046062","title":"Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Protein-Protein Interaction as a Target for Next-Generation Anti-influenza Therapeutics.","date":"2016","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27046062","citation_count":49,"is_preprint":false},{"pmid":"23644518","id":"PMC_23644518","title":"Aberrant promoter hypermethylation of PBRM1, BAP1, SETD2, KDM6A and other chromatin-modifying genes is absent or rare in clear cell RCC.","date":"2013","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/23644518","citation_count":45,"is_preprint":false},{"pmid":"32195359","id":"PMC_32195359","title":"PBRM1 mutation and preliminary response to immune checkpoint blockade treatment in non-small cell lung cancer.","date":"2020","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32195359","citation_count":44,"is_preprint":false},{"pmid":"27864835","id":"PMC_27864835","title":"Intrahepatic cholangiocarcinoma frequently shows loss of BAP1 and PBRM1 expression, and demonstrates specific clinicopathological and genetic characteristics with BAP1 loss.","date":"2017","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/27864835","citation_count":40,"is_preprint":false},{"pmid":"25465300","id":"PMC_25465300","title":"Loss of PBRM1 and BAP1 expression is less common in non-clear cell renal cell carcinoma than in clear cell renal cell carcinoma.","date":"2014","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25465300","citation_count":39,"is_preprint":false},{"pmid":"32386456","id":"PMC_32386456","title":"PB1-F2 protein of highly pathogenic influenza A (H7N9) virus selectively suppresses RNA-induced NLRP3 inflammasome activation through inhibition of MAVS-NLRP3 interaction.","date":"2020","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/32386456","citation_count":38,"is_preprint":false},{"pmid":"28418397","id":"PMC_28418397","title":"Bap180/Baf180 is required to maintain homeostasis of intestinal innate immune response in Drosophila and mice.","date":"2017","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28418397","citation_count":37,"is_preprint":false},{"pmid":"25911086","id":"PMC_25911086","title":"A germline mutation in PBRM1 predisposes to renal cell carcinoma.","date":"2015","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25911086","citation_count":36,"is_preprint":false},{"pmid":"30463209","id":"PMC_30463209","title":"A PB1-K577E Mutation in H9N2 Influenza Virus Increases Polymerase Activity and Pathogenicity in Mice.","date":"2018","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/30463209","citation_count":36,"is_preprint":false},{"pmid":"32348751","id":"PMC_32348751","title":"Pbrm1 Steers Mesenchymal Stromal Cell Osteolineage Differentiation by Integrating PBAF-Dependent Chromatin Remodeling and BMP/TGF-β Signaling.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32348751","citation_count":35,"is_preprint":false},{"pmid":"14517229","id":"PMC_14517229","title":"The PB1 domain and the PC motif-containing region are structurally similar protein binding modules.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/14517229","citation_count":35,"is_preprint":false},{"pmid":"29986887","id":"PMC_29986887","title":"PBRM1 bromodomains variably influence nucleosome interactions and cellular function.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29986887","citation_count":34,"is_preprint":false},{"pmid":"36445328","id":"PMC_36445328","title":"MUC1-C Dictates PBRM1-Mediated Chronic Induction of Interferon Signaling, DNA Damage Resistance, and Immunosuppression in Triple-Negative Breast Cancer.","date":"2023","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/36445328","citation_count":32,"is_preprint":false},{"pmid":"22336179","id":"PMC_22336179","title":"IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme.","date":"2012","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22336179","citation_count":31,"is_preprint":false},{"pmid":"25631088","id":"PMC_25631088","title":"The avian-origin PB1 gene segment facilitated replication and transmissibility of the H3N2/1968 pandemic influenza virus.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25631088","citation_count":31,"is_preprint":false},{"pmid":"25200863","id":"PMC_25200863","title":"Concurrent loss of INI1, PBRM1, and BRM expression in epithelioid sarcoma: implications for the cocontributions of multiple SWI/SNF complex members to pathogenesis.","date":"2014","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25200863","citation_count":30,"is_preprint":false},{"pmid":"23704945","id":"PMC_23704945","title":"The influenza virus protein PB1-F2 interacts with IKKβ and modulates NF-κB signalling.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23704945","citation_count":30,"is_preprint":false},{"pmid":"33216538","id":"PMC_33216538","title":"Pan-SMARCA/PB1 Bromodomain Inhibitors and Their Role in Regulating Adipogenesis.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33216538","citation_count":29,"is_preprint":false},{"pmid":"29966650","id":"PMC_29966650","title":"PB1 and UBA domains of p62 are essential for aggresome-like induced structure formation.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29966650","citation_count":29,"is_preprint":false},{"pmid":"28394406","id":"PMC_28394406","title":"PBRM1 loss is a late event during the development of cholangiocarcinoma.","date":"2017","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/28394406","citation_count":28,"is_preprint":false},{"pmid":"31714745","id":"PMC_31714745","title":"Discovery of Influenza Polymerase PA-PB1 Interaction Inhibitors Using an In Vitro Split-Luciferase Complementation-Based Assay.","date":"2019","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31714745","citation_count":28,"is_preprint":false},{"pmid":"28092369","id":"PMC_28092369","title":"Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma.","date":"2017","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28092369","citation_count":27,"is_preprint":false},{"pmid":"31077944","id":"PMC_31077944","title":"PBRM1 Regulates Stress Response in Epithelial Cells.","date":"2019","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/31077944","citation_count":27,"is_preprint":false},{"pmid":"22435813","id":"PMC_22435813","title":"Cancer and the bromodomains of BAF180.","date":"2012","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/22435813","citation_count":25,"is_preprint":false},{"pmid":"30585695","id":"PMC_30585695","title":"High affinity binding of H3K14ac through collaboration of bromodomains 2, 4 and 5 is critical for the molecular and tumor suppressor functions of PBRM1.","date":"2019","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30585695","citation_count":25,"is_preprint":false},{"pmid":"37984441","id":"PMC_37984441","title":"The PB1 and the ZZ domain of the autophagy receptor p62/SQSTM1 regulate the interaction of p62/SQSTM1 with the autophagosome protein LC3B.","date":"2024","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/37984441","citation_count":24,"is_preprint":false},{"pmid":"32323899","id":"PMC_32323899","title":"Influenza A virus PB1-F2 protein: An ambivalent innate immune modulator and virulence factor.","date":"2020","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/32323899","citation_count":24,"is_preprint":false},{"pmid":"34627641","id":"PMC_34627641","title":"The Significance of PARP1 as a biomarker for Predicting the Response to PD-L1 Blockade in Patients with PBRM1-mutated Clear Cell Renal Cell Carcinoma.","date":"2021","source":"European urology","url":"https://pubmed.ncbi.nlm.nih.gov/34627641","citation_count":24,"is_preprint":false},{"pmid":"26452128","id":"PMC_26452128","title":"Computational analysis of the mutations in BAP1, PBRM1 and SETD2 genes reveals the impaired molecular processes in renal cell carcinoma.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26452128","citation_count":24,"is_preprint":false},{"pmid":"35013001","id":"PMC_35013001","title":"PBRM1 Inactivation Promotes Upregulation of Human Endogenous Retroviruses in a HIF-Dependent Manner.","date":"2022","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/35013001","citation_count":23,"is_preprint":false},{"pmid":"33850862","id":"PMC_33850862","title":"Comprehensive analyses of PBRM1 in multiple cancer types and its association with clinical response to immunotherapy and immune infiltrates.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33850862","citation_count":23,"is_preprint":false},{"pmid":"28327121","id":"PMC_28327121","title":"BAP1 and PBRM1 in metastatic clear cell renal cell carcinoma: tumor heterogeneity and concordance with paired primary tumor.","date":"2017","source":"BMC urology","url":"https://pubmed.ncbi.nlm.nih.gov/28327121","citation_count":22,"is_preprint":false},{"pmid":"25496315","id":"PMC_25496315","title":"Frequent co-inactivation of the SWI/SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhabdoid tumours.","date":"2015","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/25496315","citation_count":22,"is_preprint":false},{"pmid":"15200852","id":"PMC_15200852","title":"Influenza A virus PB1-F2 gene in recent Taiwanese isolates.","date":"2004","source":"Emerging infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/15200852","citation_count":22,"is_preprint":false},{"pmid":"28921948","id":"PMC_28921948","title":"BAF180: Its Roles in DNA Repair and Consequences in Cancer.","date":"2017","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/28921948","citation_count":21,"is_preprint":false},{"pmid":"32093567","id":"PMC_32093567","title":"A novel EZH2 inhibitor induces synthetic lethality and apoptosis in PBRM1-deficient cancer cells.","date":"2020","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/32093567","citation_count":20,"is_preprint":false},{"pmid":"37095322","id":"PMC_37095322","title":"PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma.","date":"2023","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37095322","citation_count":19,"is_preprint":false},{"pmid":"34551289","id":"PMC_34551289","title":"PBRM1 loss in kidney cancer unbalances the proximal tubule master transcription factor hub to repress proximal tubule differentiation.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34551289","citation_count":19,"is_preprint":false},{"pmid":"36699446","id":"PMC_36699446","title":"PBRM1 mutation as a predictive biomarker for immunotherapy in multiple cancers.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36699446","citation_count":18,"is_preprint":false},{"pmid":"25978027","id":"PMC_25978027","title":"PBRM1 suppresses bladder cancer by cyclin B1 induced cell cycle arrest.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25978027","citation_count":18,"is_preprint":false},{"pmid":"23600872","id":"PMC_23600872","title":"PB1-F2 expedition from the whole protein through the domain to aa residue function.","date":"2013","source":"Acta virologica","url":"https://pubmed.ncbi.nlm.nih.gov/23600872","citation_count":18,"is_preprint":false},{"pmid":"16376336","id":"PMC_16376336","title":"Crystal structure of the PB1 domain of NBR1.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16376336","citation_count":18,"is_preprint":false},{"pmid":"36227159","id":"PMC_36227159","title":"Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening.","date":"2022","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36227159","citation_count":17,"is_preprint":false},{"pmid":"34200988","id":"PMC_34200988","title":"PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34200988","citation_count":17,"is_preprint":false},{"pmid":"35672925","id":"PMC_35672925","title":"PBRM1 deficiency oncogenic addiction is associated with activated AKT-mTOR signalling and aerobic glycolysis in clear cell renal cell carcinoma cells.","date":"2022","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35672925","citation_count":17,"is_preprint":false},{"pmid":"34447697","id":"PMC_34447697","title":"Mutational Analysis of PBRM1 and Significance of PBRM1 Mutation in Anti-PD-1 Immunotherapy of Clear Cell Renal Cell Carcinoma.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34447697","citation_count":17,"is_preprint":false},{"pmid":"32305460","id":"PMC_32305460","title":"Determinants of PB1 Domain Interactions in Auxin Response Factor ARF5 and Repressor IAA17.","date":"2020","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32305460","citation_count":17,"is_preprint":false},{"pmid":"26178300","id":"PMC_26178300","title":"PBRM1 (BAF180) protein is functionally regulated by p53-induced protein degradation in renal cell carcinomas.","date":"2015","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26178300","citation_count":16,"is_preprint":false},{"pmid":"32272772","id":"PMC_32272772","title":"Influenza PB1-F2 Inhibits Avian MAVS Signaling.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/32272772","citation_count":16,"is_preprint":false},{"pmid":"26117423","id":"PMC_26117423","title":"The BAH domain of BAF180 is required for PCNA ubiquitination.","date":"2015","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/26117423","citation_count":16,"is_preprint":false},{"pmid":"28846693","id":"PMC_28846693","title":"PBRM1 regulates proliferation and the cell cycle in renal cell carcinoma through a chemokine/chemokine receptor interaction pathway.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28846693","citation_count":16,"is_preprint":false},{"pmid":"37400502","id":"PMC_37400502","title":"PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system.","date":"2023","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37400502","citation_count":16,"is_preprint":false},{"pmid":"35169077","id":"PMC_35169077","title":"Viral PB1-F2 and host IFN-γ guide ILC2 and T cell activity during influenza virus infection.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35169077","citation_count":15,"is_preprint":false},{"pmid":"32123237","id":"PMC_32123237","title":"Deep Evolutionary History of the Phox and Bem1 (PB1) Domain Across Eukaryotes.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32123237","citation_count":15,"is_preprint":false},{"pmid":"36808431","id":"PMC_36808431","title":"PBRM1 bromodomains associate with RNA to facilitate chromatin association.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36808431","citation_count":14,"is_preprint":false},{"pmid":"33246952","id":"PMC_33246952","title":"PBRM1 and the glycosylphosphatidylinositol biosynthetic pathway promote tumor killing mediated by MHC-unrestricted cytotoxic lymphocytes.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33246952","citation_count":14,"is_preprint":false},{"pmid":"35368029","id":"PMC_35368029","title":"The RBPJ/DAPK3/UBE3A signaling axis induces PBRM1 degradation to modulate the sensitivity of renal cell carcinoma to CDK4/6 inhibitors.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35368029","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49223,"output_tokens":7281,"usd":0.128442,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16519,"output_tokens":4448,"usd":0.096897,"stage2_stop_reason":"end_turn"},"total_usd":0.225339,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"BAF180 (PBRM1) is a PBAF-specific subunit required for PBAF-mediated potentiation of nuclear receptor (RXRalpha, VDR, PPARgamma) transcriptional activation in vitro; ablation in mouse embryos causes hypoplastic ventricle development and trophoblast defects. BAF180 is recruited to promoters of target genes (S100A13, RARbeta2, CRABPII) and is required for retinoic acid response.\",\n      \"method\": \"Mouse knockout (BAF180 ablation), embryonic aggregation analysis, in vitro transcriptional activation assay, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vitro assay, KO mouse with defined phenotype, ChIP confirming promoter recruitment, multiple orthogonal methods\",\n      \"pmids\": [\"15601824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BAF180 (PBRM1) is required for epicardial epithelial-to-mesenchymal transition (EMT) and coronary vessel development; BAF180 mutant epicardial cells show compromised migration and EMT potentials, and expression of FGF, TGF, and VEGF pathway genes is downregulated in mutant hearts.\",\n      \"method\": \"BAF180 knockout mouse model, 3D collagen gel migration/EMT assay, PECAM and alpha-SMA staining, quantitative RT-PCR\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined cellular phenotype, multiple functional assays (migration, immunostaining, qRT-PCR)\",\n      \"pmids\": [\"18508041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BAF180 (PBRM1) is required for proper p21/WAF1/CIP1 expression and G1 arrest; endogenous BAF180 binds to the p21 promoter and is required for p21 induction by TGF-beta and gamma-radiation. BAF180 complementation of BAF180-mutant tumor cells causes G1 arrest dependent on p21 upregulation.\",\n      \"method\": \"Cell complementation of BAF180-mutant tumor cells, chromatin immunoprecipitation (ChIP) at p21 promoter, TGF-beta/gamma-radiation treatment, cell cycle analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct promoter binding, functional rescue by complementation, multiple stimuli tested\",\n      \"pmids\": [\"18339845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BAF180 (PBRM1) regulates p53 transcriptional activity toward a subset of p53 target genes required for replicative and oncogenic stress senescence induction. Loss of BAF180 impairs replicative senescence in primary human cells.\",\n      \"method\": \"Loss-of-function genetic screen in primary human cells, p53 transcriptional activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen with defined phenotypic readout, single lab\",\n      \"pmids\": [\"20660729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BAF180 (PBRM1) is required for centromeric cohesion in mouse and human cells. Cancer-associated BAF180 mutations fail to support cohesion, and BAF180 loss leads to dynamic chromosome instability following DNA damage.\",\n      \"method\": \"BAF180 depletion in mouse and human cells, cohesion assay, chromosome instability analysis, functional testing of tumor-derived mutants in yeast cohesion assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, tumor-derived mutants functionally tested, conservation confirmed in yeast\",\n      \"pmids\": [\"24613357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BAF180 (PBRM1) directly binds regulatory elements in the IL-10 locus and represses IL-10 transcription in Th2 cells. In the absence of BAF180, BAF250-containing BAF complexes replace it at the IL-10 locus, resulting in increased histone acetylation and CBP recruitment.\",\n      \"method\": \"BAF180-deficient mouse T cells, ChIP at IL-10 locus, histone acetylation assay, CBP recruitment analysis\",\n      \"journal\": \"BMC immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct locus binding, mechanistic follow-up with histone modifications and CBP recruitment, KO mouse model\",\n      \"pmids\": [\"22336179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BAH domains of BAF180 (PBRM1) are required for PCNA ubiquitination during S-phase after UV irradiation; the BAH domain region promotes PCNA ubiquitination independent of PBAF complex assembly and ATPase activity.\",\n      \"method\": \"Expression of BAF180 deletion mutants in cells, ubiquitinated PCNA western blot, UV irradiation assay, PBAF assembly analysis\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion analysis, functional readout (PCNA ubiquitination), single lab\",\n      \"pmids\": [\"26117423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BAF180 (PBRM1) deletion in primary mouse embryonic fibroblasts triggers cell cycle arrest and premature cellular senescence through elevated p21 expression. BAF180 binds the p21 promoter and suppresses its transcription; BAF180 deletion enhances binding of activation-associated histone modifications to the p21 promoter. Deletion of p21 rescues senescence in BAF180-deficient MEFs.\",\n      \"method\": \"Conditional somatic knockout in mice, ChIP at p21 promoter, histone modification analysis, p21 genetic rescue experiment, hematopoietic stem cell functional assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse, ChIP, genetic epistasis (p21 rescue), multiple orthogonal readouts\",\n      \"pmids\": [\"26992241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PBRM1 loss amplifies HIF1 and STAT3 transcriptional outputs driven by VHL deficiency. Combined kidney-specific deletion of Vhl and Pbrm1 (but not either alone) results in multifocal, transplantable clear cell kidney cancers in mice, with convergence on mTOR activation as a third driver event.\",\n      \"method\": \"Kidney-specific conditional knockout of Vhl and Pbrm1 in mice, transcriptional analysis, mTOR pathway analysis, tumor transplantation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in conditional KO mouse model, multiple orthogonal methods, functional transplantation confirmation\",\n      \"pmids\": [\"28329682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PBRM1 inactivation amplifies the HIF transcriptional signature in VHL-null ccRCC. BAF180 growth suppression requires formation of a canonical PBAF complex containing BRG1; a tumor-associated BAF180 mutant fails to form this complex and does not suppress growth.\",\n      \"method\": \"ccRCC cell line proliferation assays in vitro and in vivo xenograft, biochemical PBAF complex assembly assay, HIF transcriptional signature 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 — functional in vitro and in vivo assays, biochemical complex assembly, tumor mutant analysis\",\n      \"pmids\": [\"28082722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Bap1 and Pbrm1 loss (with Vhl) in PAX8-expressing cells drives ccRCC of different grades in mice; Bap1-deficient tumors are high grade with greater mTORC1 activation than Pbrm1-deficient tumors. Disrupting one Tsc1 allele in Pbrm1-deficient kidneys triggers higher grade ccRCC, implicating mTORC1 as a grade rheostat.\",\n      \"method\": \"Conditional KO mouse models with multiple Cre drivers, histological grading, mTORC1 pathway analysis, genetic epistasis (Tsc1 heterozygous deletion)\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models, genetic epistasis with Tsc1, defined histological phenotype\",\n      \"pmids\": [\"28473526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of VHL alone causes DNA replication stress and damage accumulation that constrains cellular growth; concomitant PBRM1 loss rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation. Combined Vhl/Pbrm1 deletion in mouse kidney is sufficient for fully-penetrant multifocal carcinomas.\",\n      \"method\": \"VHL/PBRM1 co-deletion in cells and conditional KO mouse, DNA replication stress assays (DNA damage markers), proliferation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis, functional replication stress assay, KO mouse model with defined phenotype\",\n      \"pmids\": [\"29229903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Drosophila Bap180 (ortholog of PBRM1/BAF180) is induced by IMD-Relish signaling in the gut and feeds back to restrain overreactive IMD signaling and repress TNF/eiger expression, maintaining intestinal innate immune homeostasis. Intestinal Baf180 targeting in mice increases susceptibility to Citrobacter rodentium infection.\",\n      \"method\": \"Drosophila intestinal Bap180 knockdown/overexpression, infection models, genetic epistasis with IMD pathway, mouse intestinal Baf180 targeting\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila genetic epistasis with defined immune phenotype, conservation in mouse model, single lab\",\n      \"pmids\": [\"28418397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PBRM1 bromodomains BD2 and BD4 mediate binding to acetylated histone peptides and modified nucleosomes. BD1 and BD5 enhance nucleosome interactions of BD2 and BD4 respectively, while BD3 attenuates them. Binding-pocket missense mutations in BD4 (but not BD2) found in ccRCC disrupt PBRM1-chromatin interactions and accelerate ccRCC cell proliferation.\",\n      \"method\": \"Histone microarrays, nucleosome binding assays with recombinant and cellular nucleosomes, BD missense mutant analysis, ccRCC cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with histone microarrays and nucleosomes, mutagenesis, functional cellular readout\",\n      \"pmids\": [\"29986887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PBRM1 acts as a reader of p53 acetylation at lysine 382 (K382Ac) through its bromodomain 4 (BD4). Mutations on key BD4 residues disrupt recognition of p53 K382Ac, reduce p53 binding to target promoters (including CDKN1A/p21), impair p53 transcriptional activity, and abolish PBRM1 tumor suppressor function in kidney cancer xenografts.\",\n      \"method\": \"Biochemical binding assay (PBRM1 BD4 with K382Ac p53 peptide), ChIP at CDKN1A promoter, BD4 mutagenesis, p53 transcriptional reporter, xenograft tumor suppression assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical binding, mutagenesis, ChIP, functional xenograft, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31863007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Full-length PBRM1 (but not individual bromodomains) strongly binds H3K14ac; BDs 2, 4, and 5 collaborate for high-affinity H3K14ac binding. Simultaneous point mutations in BDs 2, 4, and 5 prevent H3K14ac recognition, alter promoter binding, change gene expression, and cause PBRM1 to relocalize to the cytoplasm. Tumor-derived BD2 mutations alone weaken H3K14ac binding and abolish tumor suppressor activity in xenografts.\",\n      \"method\": \"Purified BD protein binding assays (quantitative), full-length PBRM1 H3K14ac binding assay, BD mutagenesis, ChIP, transcriptional profiling, xenograft tumor suppression, subcellular localization by imaging\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with purified proteins, mutagenesis, ChIP, localization, xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"30585695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PBRM1/Pbrm1 deficiency reduces binding of BRG1 to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and subsequent expression of IFNγ target genes, leading to a less immunogenic tumor microenvironment.\",\n      \"method\": \"ChIP (BRG1 at Ifngr2 promoter), STAT1 phosphorylation assay, PBRM1-deficient cell lines and murine models, patient cohort analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct promoter binding, STAT1 phosphorylation as mechanistic readout, in vitro and in vivo models\",\n      \"pmids\": [\"32358509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BMPs and osteogenic signals in mesenchymal stromal cells selectively induce PBAF components Pbrm1, Arid2, and Brd7. Pbrm1/PBAF deficiency impairs Smad1/5/8 activation through locus-specific epigenomic remodeling involving Pbrm1 bromodomains, and transcriptionally downregulates Bmpr/TgfβrII expression. Gain of function of BmprIβ/TgfβrII in PBAF-deficient MSCs partly restores osteogenesis.\",\n      \"method\": \"Conditional Pbrm1 loss in MSCs, ATAC-seq/ChIP-seq (bromodomain-specific), Smad1/5/8 activation assay, BmprIβ/TgfβrII rescue experiment, in vivo ossification assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — locus-specific chromatin analysis, Smad activation assay, genetic rescue, single lab\",\n      \"pmids\": [\"32348751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PBRM1 deficiency causes elevated replication stress, micronuclei, and R-loops in cells; multiple R-loop processing factors are downregulated in PBRM1-defective tumor cells. PARP and ATR inhibitors are synthetic lethal with PBRM1 deficiency, and exogenous RNase H1 expression reverses PARP inhibitor sensitivity in PBRM1-deficient cells, implicating R-loop accumulation as a mechanistic basis.\",\n      \"method\": \"Functional genomic screens, R-loop quantification, replication stress markers, quantitative mass spectrometry of R-loop factors, RNase H1 rescue experiment, xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal functional screens, MS proteomics, genetic rescue (RNase H1), in vitro and in vivo models\",\n      \"pmids\": [\"33888468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAX8 (master proximal tubule transcription factor) recruits PBRM1/PBAF specifically (not BAF) as a coactivator. In RCC cells lacking PBRM1, corepressors dominate the PAX8 hub, repressing key PAX8 target genes with loss of H3K27 acetylation. Re-introduction of PBRM1, or depletion of opposing corepressors, restores PAX8 target gene expression and induces terminal epithelial differentiation.\",\n      \"method\": \"Unbiased proteomics (PAX8 interactome), reciprocal Co-IP (PAX8-PBRM1/PBAF), ChIP (H3K27ac, H3K4me3), PBRM1 re-expression, siRNA corepressor depletion, terminal differentiation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, MS proteomics, ChIP, functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"34551289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PBRM1 cooperates with YTHDF2 (an m6A reader) to control HIF-1α protein translation; PBRM1 (but not BRG1) interacts with YTHDF2, and HIF-1α mRNA is m6A-modified and bound by both PBRM1 and YTHDF2. PBRM1 is required for YTHDF2 binding to HIF-1α mRNA. This represents a SWI/SNF-independent function for PBRM1.\",\n      \"method\": \"Co-IP (PBRM1-YTHDF2 interaction), RNA immunoprecipitation (HIF-1α mRNA), polysome/translation assay, PBRM1 KD with HIF-1α protein/mRNA analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, RNA-IP, translation assay, single lab with single mechanistic paper\",\n      \"pmids\": [\"34200988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci (distal enhancers with NF-κB motifs), activating the pro-tumorigenic NF-κB pathway. PBRM1-deficient PBAF retains SMARCA4-ARID2 association but has loosely tethered BRD7. SMARCA4 ATPase activity maintains chromatin occupancy of RELA at newly acquired sites, and proteasome inhibitor bortezomib suppresses RELA occupancy and delays PBRM1-deficient tumor growth.\",\n      \"method\": \"ChIP-seq (PBAF subunit redistribution), Co-IP (PBAF complex composition), SMARCA4 ATPase mutant analysis, RELA ChIP, bortezomib treatment in vivo xenograft\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq genome-wide, Co-IP complex composition, ATPase mutant, in vivo therapeutic experiment, multiple orthogonal methods\",\n      \"pmids\": [\"37095322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PBRM1 is degraded via proteasomal degradation induced by p53 activation. p53-dependent PBRM1 regulation is post-translational (not transcriptional), as demonstrated by pulse-chase experiments and proteasome inhibitor rescue.\",\n      \"method\": \"siRNA knockdown of p53, pulse-chase experiment, proteasome inhibitor treatment, RCC cell lines and ex vivo tissue\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulse-chase establishing post-translational mechanism, proteasome inhibitor rescue, siRNA validation; single lab\",\n      \"pmids\": [\"26178300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBE3A (an E3 ubiquitin ligase) binds PBRM1 and regulates its stability via ubiquitin-mediated proteasomal degradation. RBPJ/DAPK3 modulates UBE3A E3 ligase activity by interfering with PKA phosphorylation of UBE3A. The RBPJ/DAPK3/UBE3A axis controls PBRM1 protein levels and downstream p21 expression, affecting RCC sensitivity to CDK4/6 inhibitors.\",\n      \"method\": \"Unbiased mass spectrometry of PBRM1 interactome, Co-IP (PBRM1-UBE3A), ubiquitination assay, PKA phosphorylation of UBE3A, PBRM1 stability assay, CDK4/6 inhibitor sensitivity assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction, Co-IP, ubiquitination assay, functional drug sensitivity readout; single lab\",\n      \"pmids\": [\"35368029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PBRM1 inactivation upregulates human endogenous retroviruses (hERVs) in a HIF1α- and HIF2α-dependent manner in ccRCC, as confirmed by in vitro PBRM1, HIF1A, and HIF2A silencing followed by RNA sequencing.\",\n      \"method\": \"RNA sequencing after siRNA knockdown of PBRM1/HIF1A/HIF2A, TCGA and IMmotion150 cohort analysis\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with genetic perturbation, mechanistic epistasis via HIF knockdown, single lab\",\n      \"pmids\": [\"35013001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MUC1-C is necessary for PBRM1 expression and forms a nuclear complex with PBRM1 in triple-negative breast cancer cells. MUC1-C and PBRM1 cooperatively drive STAT1 and IRF1 expression by increasing chromatin accessibility at their gene promoters (shown by RNA-seq and ATAC-seq), promoting chronic IFN pathway activation and DNA damage resistance.\",\n      \"method\": \"Co-IP (MUC1-C/PBRM1 nuclear complex), RNA-seq, ATAC-seq, MUC1-C knockdown, PBRM1 dependency analysis, DNA damage assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ATAC-seq, RNA-seq with KD, multiple readouts; single lab\",\n      \"pmids\": [\"36445328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PBRM1 bromodomains BD2 and BD4 bind double-stranded RNA elements in addition to acetylated histones. Disruption of the RNA-binding pocket compromises PBRM1 chromatin binding and inhibits PBRM1-mediated cellular growth suppression effects.\",\n      \"method\": \"In vitro RNA binding assays (BD2, BD4), RNA-binding pocket mutagenesis, chromatin binding assay, cellular growth assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical RNA binding assay, mutagenesis of binding pocket, functional cellular readout; single lab\",\n      \"pmids\": [\"36808431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PBRM1 loss in tumor cells causes resistance to MHC-unrestricted cytotoxic lymphocyte (NK cell) killing in genome-wide genetic screens. PBRM1 and the GPI biosynthetic pathway regulate NK cell receptor ligands on tumor cells and promote cytolytic granule secretion in cytotoxic lymphocytes.\",\n      \"method\": \"Genome-wide CRISPR/genetic screen, NK cell killing assay, NK cell receptor ligand expression analysis, cytolytic granule secretion assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen, functional NK killing assay, ligand expression analysis; single study\",\n      \"pmids\": [\"33246952\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PBRM1/BAF180 is the chromatin-targeting subunit of the PBAF SWI/SNF complex, tethering PBAF to chromatin through cooperative bromodomain-mediated recognition of acetylated histones (H3K14ac via BDs 2/4/5, and p53-K382Ac via BD4), thereby regulating transcription of genes involved in p21/cell cycle control, HIF-target gene expression, NF-κB signaling, IFN-γ/STAT1 signaling, and cellular differentiation; PBRM1 loss leads to ectopic PBAF redistribution to NF-κB enhancers, amplified HIF transcriptional output, replication stress and R-loop accumulation, impaired cohesion and genome stability, and altered tumor immune recognition—while PBRM1 protein stability is itself regulated by p53-induced UBE3A-mediated proteasomal degradation and by a novel SWI/SNF-independent interaction with YTHDF2 to facilitate HIF-1α mRNA translation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PBRM1/BAF180 is the chromatin-targeting subunit of the PBAF SWI/SNF chromatin-remodeling complex, controlling transcriptional programs that govern cell-cycle arrest, cellular differentiation, genome stability, and immune recognition [#0, #2, #19]. It tethers PBAF to chromatin through cooperative bromodomain recognition of acetylated histones: full-length PBRM1 binds H3K14ac via the collaborative action of bromodomains BD2, BD4 and BD5, and tumor-derived bromodomain mutations weaken this interaction, mislocalize PBRM1, and abolish its tumor-suppressor activity [#13, #15]. The same bromodomains read additional acetyl marks and nucleic acids—BD4 recognizes p53 acetylated at K382 to promote p53 binding at target promoters including CDKN1A/p21, and BD2/BD4 also bind double-stranded RNA elements required for chromatin engagement [#14, #26]. Through these targeting activities PBRM1 binds the p21 promoter to enforce p21-dependent G1 arrest and senescence, supports centromeric cohesion, and restrains replication stress and R-loop accumulation [#2, #4, #7, #18]. In clear cell renal carcinoma, combined PBRM1 and VHL loss amplifies HIF and STAT3 transcriptional output, relieves VHL-induced replication stress, and drives tumorigenesis with convergence on mTORC1 [#8, #9, #11, #10]. PBRM1 loss also causes ectopic PBAF redistribution to NF-\\u03baB enhancers and reduces BRG1 occupancy at the IFN\\u03b3 receptor promoter, shaping a less immunogenic tumor microenvironment [#21, #16]. Beyond its remodeling role, PBRM1 has a SWI/SNF-independent function cooperating with the m6A reader YTHDF2 to control HIF-1\\u03b1 mRNA translation, and its protein stability is governed by p53-induced, UBE3A-mediated proteasomal degradation [#20, #22, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established PBRM1 as the defining PBAF-specific subunit and a chromatin-recruited transcriptional coactivator, framing all later mechanistic work.\",\n      \"evidence\": \"Mouse knockout, in vitro nuclear-receptor transcription assay, and ChIP at target promoters\",\n      \"pmids\": [\"15601824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of promoter targeting not defined\", \"Did not address tumor-suppressor function\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed PBRM1 controls developmental cell behaviors and links it to p21-dependent cell-cycle arrest, revealing both differentiation and growth-control roles.\",\n      \"evidence\": \"Knockout mouse epicardial EMT/migration assays and ChIP-coupled p21 induction in complemented tumor cells\",\n      \"pmids\": [\"18508041\", \"18339845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PBRM1 represses vs. activates p21 across contexts unresolved\", \"Direct chromatin-reading determinants not yet mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected PBRM1 to p53-dependent senescence, positioning it within stress-response transcriptional control.\",\n      \"evidence\": \"Loss-of-function screen in primary human cells with p53 transcriptional readouts\",\n      \"pmids\": [\"20660729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which p53 targets are PBRM1-dependent not fully defined\", \"Single-lab functional screen\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified non-transcriptional and lineage-specific roles—centromeric cohesion/genome stability and direct repression of the IL-10 locus in Th2 cells, with subunit competition by BAF250.\",\n      \"evidence\": \"Cohesion and chromosome-instability assays with tumor-mutant testing; ChIP and histone-acetylation/CBP analysis in KO T cells\",\n      \"pmids\": [\"24613357\", \"22336179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PBRM1 to cohesin loading unknown\", \"Generality of BAF/PBAF subunit swapping across loci untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reinforced the p21 axis using conditional knockout and genetic epistasis, showing PBRM1 loss causes premature senescence rescuable by p21 deletion.\",\n      \"evidence\": \"Conditional mouse KO, ChIP, histone-modification analysis, and p21 genetic rescue\",\n      \"pmids\": [\"26992241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PBRM1 toggles between p21 repression and induction unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined PBRM1 as a renal tumor suppressor whose loss with VHL drives ccRCC by amplifying HIF/STAT3 output, relieving replication stress, and converging on mTORC1, and showed growth suppression requires intact PBAF assembly.\",\n      \"evidence\": \"Kidney-specific Vhl/Pbrm1 conditional KO mice, biochemical PBAF assembly assays, replication-stress markers, and mTORC1/Tsc1 epistasis\",\n      \"pmids\": [\"28329682\", \"28082722\", \"29229903\", \"28473526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin targets mediating HIF amplification not enumerated\", \"Mechanism of replication-stress rescue at the molecular level incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended PBRM1 function to innate immune homeostasis and BAH-domain-dependent PCNA ubiquitination, showing complex- and domain-specific activities.\",\n      \"evidence\": \"Drosophila IMD-pathway epistasis with mouse infection model; BAF180 deletion-mutant PCNA-ubiquitination assays after UV\",\n      \"pmids\": [\"28418397\", \"26117423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BAH-domain mechanism of promoting PCNA ubiquitination undefined\", \"Single-lab domain-deletion analyses\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the molecular logic of PBRM1 chromatin targeting: multivalent bromodomain reading of H3K14ac and p53-K382Ac, with tumor mutations disrupting binding and tumor suppression.\",\n      \"evidence\": \"Purified bromodomain and full-length binding assays, histone microarrays, BD mutagenesis, ChIP, transcriptional profiling, and xenografts\",\n      \"pmids\": [\"29986887\", \"30585695\", \"31863007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of inter-bromodomain cooperativity not solved\", \"Full acetyl-mark repertoire incompletely mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked PBRM1 to tumor immune recognition through both IFN\\u03b3/STAT1 signaling and NK-cell-mediated killing, establishing an immunological dimension to its loss.\",\n      \"evidence\": \"ChIP of BRG1 at Ifngr2, STAT1 phosphorylation assays, and genome-wide CRISPR NK-killing screens with ligand/granule readouts\",\n      \"pmids\": [\"32358509\", \"33246952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from chromatin to NK ligand expression incomplete\", \"Single-study findings for each axis\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined PBRM1 as a guardian against replication stress/R-loops and a context-specific PAX8 coactivator, while revealing a SWI/SNF-independent translational role via YTHDF2.\",\n      \"evidence\": \"Functional genomic screens with RNase H1 rescue and synthetic-lethality assays; PAX8 interactome proteomics with reciprocal Co-IP and ChIP; PBRM1-YTHDF2 Co-IP/RNA-IP and translation assays\",\n      \"pmids\": [\"33888468\", \"34551289\", \"34200988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which R-loop processing factors are direct PBRM1 transcriptional targets unclear\", \"YTHDF2 cooperation rests on single-lab Co-IP/RNA-IP\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed PBRM1 loss produces gain-of-function via ectopic PBAF redistribution to NF-\\u03baB enhancers and defined how PBRM1 protein levels are controlled by p53-induced UBE3A-mediated degradation.\",\n      \"evidence\": \"ChIP-seq of PBAF subunit redistribution with SMARCA4 ATPase mutants and bortezomib xenografts; pulse-chase, proteasome-inhibitor rescue, and PBRM1-UBE3A interactome/ubiquitination assays\",\n      \"pmids\": [\"37095322\", \"26178300\", \"35368029\", \"35013001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants directing ectopic PBAF to NF-\\u03baB motifs unresolved\", \"Upstream signals coupling p53 to UBE3A-PBRM1 turnover incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened PBRM1's binding repertoire to double-stranded RNA and identified a MUC1-C partnership driving IFN-pathway transcription in breast cancer, indicating roles beyond renal cancer.\",\n      \"evidence\": \"In vitro RNA-binding and binding-pocket mutagenesis with chromatin/growth readouts; MUC1-C/PBRM1 Co-IP with RNA-seq and ATAC-seq\",\n      \"pmids\": [\"36808431\", \"36445328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of RNA binding in chromatin targeting vs. other processes unclear\", \"MUC1-C cooperation from a single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PBRM1's distinct activities—bromodomain acetyl/RNA reading, PBAF tethering, SWI/SNF-independent translation, and protein turnover—are integrated to specify locus selection and context-dependent tumor suppression versus gain-of-function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length PBRM1 engaging the nucleosome\", \"Mechanism directing ectopic PBAF to oncogenic enhancers unknown\", \"Integration of chromatin and RNA/translational functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [13, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 14, 19]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [26, 20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 15, 25]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 15, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 19]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 9, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 27, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18, 6]}\n    ],\n    \"complexes\": [\"PBAF SWI/SNF complex\"],\n    \"partners\": [\"SMARCA4\", \"ARID2\", \"BRD7\", \"TP53\", \"YTHDF2\", \"UBE3A\", \"PAX8\", \"MUC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}