{"gene":"BRD7","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2008,"finding":"BRD7 is a novel subunit of the PBAF (Polybromo-associated BRG1-associated factor) SWI/SNF chromatin-remodeling complex, distinct from the BAF complex; knockdown of BRD7 (PBAF-specific) and ARID1A (BAF-specific) differentially and sometimes antagonistically regulate SWI/SNF target genes, and SWI/SNF affects recruitment of preinitiation complex components at target promoters.","method":"Mass spectrometry-based complex purification, shRNA knockdown, gene expression profiling, preinitiation complex recruitment assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical complex identification by MS, functional validation by shRNA with defined transcriptional readouts, replicated in ESCs and differentiated cells","pmids":["18809673"],"is_preprint":false},{"year":2010,"finding":"BRD7 physically interacts with p53 and p300, is recruited to p53 target gene promoters, and is required for efficient p53-mediated transcription of a subset of target genes; BRD7 affects histone acetylation and p53 acetylation at these promoters, supporting oncogene-induced senescence.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, luciferase reporter assays, senescence assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with p53 and p300, ChIP showing promoter recruitment, functional senescence readout, replicated in multiple cell lines","pmids":["20228809","20660729"],"is_preprint":false},{"year":2010,"finding":"BRD7 directly binds BRCA1 (identified by yeast two-hybrid, confirmed by co-immunoprecipitation of endogenous proteins), and is required for BRCA1-mediated transcriptional regulation; BRD7 depletion prevents recruitment of BRCA1 and Oct-1 to the ESR1 promoter, reducing ERα expression, without affecting recruitment of other SWI/SNF subunits (BRG1, BAF155, BAF57) or RNA Pol II.","method":"Yeast two-hybrid, endogenous co-immunoprecipitation, ChIP, microarray expression profiling, shRNA knockdown","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid confirmed by endogenous Co-IP, ChIP showing promoter occupancy, specific mechanistic distinction from other SWI/SNF subunits","pmids":["20215511"],"is_preprint":false},{"year":2006,"finding":"BRD7's bromodomain binds acetylated histone H3 (specifically H3K14ac), co-localizes with acetylated H3 in the nucleus, and this interaction is required for BRD7-mediated transcriptional regulation of E2F3 and inhibition of G1-S cell cycle progression; a bromodomain-deleted BRD7 mutant fails to bind acetylated H3 peptide and loses these functions.","method":"Co-localization immunofluorescence, histone peptide pull-down, bromodomain deletion mutant analysis, luciferase reporter assay, flow cytometry","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro peptide binding with mutagenesis, functional validation by reporter assay and cell cycle analysis in single lab","pmids":["16265664"],"is_preprint":false},{"year":2007,"finding":"NMR solution structure of the BRD7 bromodomain reveals a typical left-handed four-helix bundle topology; NMR titration experiments show it binds with weak affinity to acetylated lysine peptides from H3 (K9ac, K14ac) and H4 (K8ac, K12ac, K16ac), lacking inherent binding specificity among these marks in vitro.","method":"NMR spectroscopy (structure determination and titration)","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional binding characterization, single lab but rigorous structural method","pmids":["17498659"],"is_preprint":false},{"year":2006,"finding":"BRD7 contains a functional nuclear localization signal (NLS) spanning amino acids 65–96 composed of bipartite nuclear targeting sequences; deletion of the NLS shifts BRD7 localization from nucleus to cytoplasm and abolishes its ability to regulate cyclin D1, E2F3 expression, and G1-S cell cycle progression.","method":"GFP fusion constructs, deletion mutagenesis, fluorescence microscopy, western blot, flow cytometry","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutagenesis with GFP reporters and functional cell cycle readouts, single lab with multiple orthogonal methods","pmids":["16475162"],"is_preprint":false},{"year":2014,"finding":"BRD7 interacts with the inter-SH2 (iSH2) domain of p85α (PI3K regulatory subunit) via a conserved C-terminal region, facilitates nuclear translocation of p85α, depletes cytosolic p85/p110 complexes, and thereby reduces p110 protein stability and PI3K/Akt pathway signaling; BRD7 and p110 compete for binding to p85.","method":"Co-immunoprecipitation, domain mapping, RNAi knockdown, Akt phosphorylation assays, subcellular fractionation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, RNAi gain/loss of function, mechanistic competition model validated by multiple biochemical approaches","pmids":["24657164"],"is_preprint":false},{"year":2014,"finding":"BRD7 interacts with regulatory subunits of PI3K (p85α and p85β) and promotes nuclear translocation of both p85 isoforms and the spliced form of XBP1 (XBP1s); BRD7 deficiency blocks nuclear translocation of XBP1s, impairing the unfolded protein response (UPR); restoring hepatic BRD7 in obese mice improves XBP1s nuclear translocation and glucose homeostasis.","method":"Co-immunoprecipitation, subcellular fractionation, in vivo mouse models (adenoviral BRD7 restoration), glucose tolerance tests","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, subcellular fractionation, and in vivo rescue experiment with functional metabolic readout, replicated across cell lines and mouse models","pmids":["24836559"],"is_preprint":false},{"year":2003,"finding":"BRD7 (Celtix-1/BP75) forms a complex with the heterogeneous nuclear ribonucleoprotein E1B-AP5 both in vivo and in vitro; disruption of this complex increases E1B-AP5 transcriptional repression activity and converts E1B-AP5 from an activator to a strong repressor of hormone-dependent promoters; BRD7 bromodomain binds histones H2A, H2B, H3, and H4, and a triple complex of E1B-AP5, BRD7, and histones was demonstrated.","method":"Yeast two-hybrid, in vivo and in vitro co-immunoprecipitation, GST pull-down, luciferase reporter assays, deletion mutagenesis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro and in vivo binding confirmed, GST pull-down, functional transcriptional readout with mutagenesis, single lab with multiple orthogonal methods","pmids":["12489984"],"is_preprint":false},{"year":2000,"finding":"BRD7 (Celtix-1) interacts with IRF-2 via the C-terminus of IRF-2, as established by yeast two-hybrid and GST pull-down; a subset of BRD7/Celtix-1 co-localizes with hyperacetylated histones H3/H4 and the hyperphosphorylated (active) form of RNA Pol II in the nucleus.","method":"Yeast two-hybrid, GST pull-down, immunofluorescence co-localization","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid confirmed by GST pull-down, immunofluorescence co-localization with active chromatin marks, single lab","pmids":["11025449"],"is_preprint":false},{"year":1999,"finding":"BP75 (BRD7) was identified through interaction with the first PDZ domain of protein tyrosine phosphatase PTP-BL in a yeast two-hybrid screen; both BP75 and a PTP-BL PDZ domain construct localize primarily to the nucleus.","method":"Yeast two-hybrid, subcellular localization by immunofluorescence","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid identification with localization data, no functional validation of interaction consequence","pmids":["10526152"],"is_preprint":false},{"year":2003,"finding":"BP75 (BRD7) directly interacts with Dvl-1 (Dishevelled-1), enhances TCF-dependent gene expression induced by Dvl-1, facilitates dephosphorylation of GSK-3β at Tyr216 thereby inhibiting its kinase activity, and synergizes with Dvl-1 to promote nuclear translocation of β-catenin.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, TCF luciferase reporter assay, GSK-3β kinase assay, β-catenin localization","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in mammalian cells, functional reporter and kinase activity assays, single lab with multiple orthogonal methods","pmids":["12941796"],"is_preprint":false},{"year":2009,"finding":"BRD7 interacts with TRIM24/TIF1α and represses TRIM24-enhanced androgen receptor (AR) transactivation activity, as measured by luciferase reporter assay in prostate cancer cells.","method":"Co-immunoprecipitation, luciferase reporter assay","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and reporter assay, single lab, no domain mapping or rescue experiment","pmids":["19909775"],"is_preprint":false},{"year":2004,"finding":"Ectopic BRD7 expression in NPC cells inhibits G1-S progression and transcriptionally regulates molecules in the Ras/MEK/ERK and Rb/E2F pathways; BRD7 negatively regulates E2F3 promoter activity.","method":"Tet-on inducible expression, cell cycle cDNA array, luciferase reporter assay, flow cytometry","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system with cell cycle array and promoter reporter assay, multiple readouts in single lab","pmids":["15137061"],"is_preprint":false},{"year":2019,"finding":"PARP-1 binds to BRD7 and poly(ADP-ribosyl)ates it; this modification enhances BRD7 ubiquitination and degradation through the PAR-binding E3 ubiquitin ligase RNF146, leading to BRD7 degradation in response to DNA damage-inducing chemotherapy.","method":"Co-immunoprecipitation, PAR assay (PARylation), ubiquitination assay, RNF146 knockdown, western blot for protein stability","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, direct PARylation assay, ubiquitination assay, genetic knockdown of E3 ligase, multiple orthogonal methods in single lab","pmids":["30940648"],"is_preprint":false},{"year":2014,"finding":"BRD7 forms a complex with the APC/C (anaphase-promoting complex/cyclosome) and is degraded by APC/C(Cdh1) and APC/C(Cdc20) during the cell cycle; a BRD7 mutant resistant to APC/C-mediated degradation more efficiently suppresses osteosarcoma proliferation and tumor growth.","method":"Co-immunoprecipitation, protein stability assay, APC/C inhibitor (proTAME), APC/C degradation-resistant mutant, in vitro and in vivo tumor growth assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with APC/C, functional mutant validation, in vivo tumor model, single lab","pmids":["24840027"],"is_preprint":false},{"year":2020,"finding":"BRD7 expression is increased by inhibition of the ubiquitin-proteasome pathway upon ferroptosis induction; elevated BRD7 promotes p53 mitochondrial translocation via direct binding to the p53 N-terminal transactivation domain (TAD); site-directed mutation of p53 serine 392 blocks BRD7-p53 binding and prevents p53 mitochondrial translocation and ferroptosis; mitochondrial p53 then interacts with SLC25A28 to enhance its activity, leading to iron accumulation and ferroptosis.","method":"CRISPR/Cas9 knockout, BRD7 overexpression plasmid, co-immunoprecipitation, site-directed mutagenesis, subcellular fractionation, SLC25A28 knockdown","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mutagenesis, CRISPR KO and OE with mechanistic rescue, subcellular fractionation, multiple orthogonal methods in single lab","pmids":["32863216"],"is_preprint":false},{"year":2020,"finding":"BRD7 is recruited to DNA double-strand break (DSB) sites via ATM-mediated phosphorylation; at DSBs, BRD7 joins PRC2 and NuRD complexes and recruits E3 ubiquitin ligase RNF168, leading to transcriptional repression at active transcription sites flanking DSBs and facilitating DNA repair.","method":"Co-immunoprecipitation, ChIP, immunofluorescence, ATM inhibitor treatment, phosphorylation site mapping, RNF168 recruitment assay, DNA repair assays","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with PRC2/NuRD/RNF168, ChIP, ATM phosphorylation mapping, functional DSB repair assays, multiple orthogonal methods","pmids":["33101843"],"is_preprint":false},{"year":2020,"finding":"BRD7 interacts with YB1 via its N-terminus binding to the C-terminus of YB1; BRD7 decreases YB1 expression by negatively regulating YB1 phosphorylation at Ser102, promoting its proteasomal degradation, thereby suppressing YB1-induced epithelial-mesenchymal transition (EMT), invasion, and metastasis in breast cancer.","method":"Co-immunoprecipitation with mass spectrometry, deletion mutant mapping, phosphorylation assay, ubiquitination/proteasome assay, in vitro migration/invasion assays, xenograft and metastatic mouse models","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identification, reciprocal Co-IP domain mapping, phosphorylation and proteasome assays, in vivo rescue, multiple orthogonal methods","pmids":["32028981"],"is_preprint":false},{"year":2008,"finding":"BRD7 interacts with BRD2 (co-immunoprecipitation confirmed in mammalian cells); the region from amino acids 430–798 of BRD2 is critical for this interaction; BRD2 localizes in the nucleus in diffuse and dotted patterns.","method":"Co-immunoprecipitation, GFP fluorescence, deletion mutant analysis","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with domain mapping, limited functional follow-up on interaction consequence","pmids":["16786191"],"is_preprint":false},{"year":2008,"finding":"The centrosome-associated protein Ceap-16/BLOS2 directly interacts with BRD7 via BRD7's C-terminus and Ceap-16's central region; this interaction translocates Ceap-16 from cytoplasm to nucleus, where it selectively inhibits BRD7's transcriptional suppression of target genes (E2F3, cyclin A); a triple complex of Ceap-16, BRD7, and histones H3/H4 was demonstrated.","method":"Co-immunoprecipitation (in vitro and in vivo), domain mapping, reporter assays, localization studies","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro Co-IP with domain mapping, triple complex demonstrated, functional transcriptional readout, single lab","pmids":["18329849"],"is_preprint":false},{"year":2016,"finding":"BRD7 knockout mice display an anti-inflammatory phenotype deficiency: BRD7-deficient MEF cells show increased NF-κB (p65) cytoplasm-to-nucleus translocation and elevated inflammatory cytokine expression (IL-6, TNF-α, CXCL-1, iNOS) after LPS stimulation; in vivo, BRD7 KO mice show increased susceptibility to DSS-induced colitis with higher NF-κB nuclear translocation, indicating BRD7 inhibits NF-κB activation during early acute inflammation.","method":"BRD7 knockout mouse model, MEF cells, LPS stimulation, NF-κB reporter assay, subcellular fractionation, DSS-induced colitis model","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vitro and in vivo models, NF-κB reporter and fractionation, multiple readouts, single lab","pmids":["27374794"],"is_preprint":false},{"year":2016,"finding":"Homozygous BRD7 knockout results in complete male infertility with spermatogenesis arrest at step 13, deformed acrosomal formation, degenerative elongating spermatids, increased apoptosis (TUNEL, annexin V, p53), and elevated DNA damage marker γH2AX; BRD7 is highly expressed in testis and localized to germ cells from pachytene to round spermatid stage.","method":"BRD7 knockout mouse model, histology, TUNEL assay, western blot for apoptosis/DNA damage markers, immunohistochemistry","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined histological and molecular phenotype, multiple readouts, single lab","pmids":["26878912"],"is_preprint":false},{"year":2015,"finding":"BRD7 knockout impairs cognitive behavior (but not emotional behavior) and reduces synaptic plasticity-related protein expression, neuronal spine density, and dendritic branching specifically in the medial prefrontal cortex (not hippocampus).","method":"BRD7 knockout mouse model, behavioral battery tests, western blot for synaptic proteins, neuronal morphology analysis","journal":"Behavioural brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with behavioral phenotype and molecular/morphological readouts, region-specific effect validated, single lab","pmids":["25721744"],"is_preprint":false},{"year":2016,"finding":"BRD7 deficiency leads to embryonic lethality in homozygous knockout mice at mid-gestation (prior to E16.5), establishing an essential developmental role; heterozygous knockdown causes mild changes in glucose metabolism.","method":"Homozygous and heterozygous BRD7 knockout mouse models, embryo developmental staging, glucose metabolism assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with clear developmental lethal phenotype and metabolic readouts, single lab","pmids":["27444544"],"is_preprint":false},{"year":2017,"finding":"BRD7 increases phosphorylation of GSK3β at Ser9 in response to insulin, with this effect occurring even in the absence of AKT activity; BRD7 also mediates phosphorylation of S6K and downstream 4E-BP1; liver-specific BRD7 knockout mice show impaired mTORC1 activity on its downstream targets.","method":"BRD7 overexpression, AKT inhibitor, liver-specific BRD7 KO mice, phosphorylation assays (western blot), in vitro and in vivo models","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and OE with mechanistic dissection of pathway, AKT inhibitor experiment, single lab","pmids":["29127434"],"is_preprint":false},{"year":2018,"finding":"BRD7 directly interacts with HIF1α and facilitates its degradation via the ubiquitin-proteasome pathway; this reduces LDHA expression and aerobic glycolysis (Warburg effect) in breast cancer cells; bromodomain of BRD7 is required for this activity.","method":"Co-immunoprecipitation, ubiquitination assay, bromodomain deletion mutant, LDHA rescue experiment, glycolysis assays, in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, bromodomain mutant, functional rescue, in vivo validation, single lab","pmids":["29725006"],"is_preprint":false},{"year":2024,"finding":"TRIM28 acts as an E3 ubiquitin ligase for BRD7; the Coiled-Coil region of TRIM28 binds the N-terminal region of BRD7, mediating K48-linked ubiquitination of BRD7 at K21, leading to proteasomal degradation of BRD7 and promoting breast cancer progression.","method":"Co-immunoprecipitation with mass spectrometry, domain mapping, ubiquitination assay (K48 linkage), site-directed mutagenesis (K21), protein stability assay, in vitro and in vivo cancer models","journal":"Cellular oncology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS, domain mapping, K48-specific ubiquitination and K21 site mutagenesis, in vivo rescue, multiple orthogonal methods","pmids":["39222175"],"is_preprint":false},{"year":2025,"finding":"TRIM25 acts as an E3 ubiquitin ligase for BRD7; the PRYSPRY region of TRIM25 binds the N-terminal region of BRD7, increasing K48-linked ubiquitination at K119 and promoting BRD7 proteasomal degradation; this leads to activation of YB1/Bcl-2 signaling, promoting breast cancer malignant progression and paclitaxel resistance.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linked, K119 site), domain mapping, protein stability assay, rescue experiment with BRD7 restoration, in vitro and in vivo models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, K48-ubiquitin and K119 site specificity, functional rescue assays, single lab","pmids":["41315221"],"is_preprint":false},{"year":2022,"finding":"BRD7 stabilizes p53 protein by inhibiting AKT-dependent phosphorylation of MDM2 (via the BRD7 bromodomain), thereby reducing phospho-MDM2 binding to p53 and decreasing p53 ubiquitination; this mechanism requires the BRD7 bromodomain.","method":"Co-immunoprecipitation, phosphorylation assay, ubiquitination assay, bromodomain deletion mutant, AKT inhibition, p53 knockdown rescue, in vivo xenograft","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with bromodomain mutant, phosphorylation and ubiquitination assays, mechanistic rescue, single lab","pmids":["35371302"],"is_preprint":false},{"year":2021,"finding":"In colorectal cancer, BRD7 interacts with c-Myc and stabilizes c-Myc protein by inhibiting its ubiquitin-proteasome-dependent degradation; restoration of c-Myc in BRD7-silenced CRC cells rescues cell proliferation and tumor growth.","method":"Co-immunoprecipitation, ubiquitination assay, c-Myc rescue experiment, in vitro and in vivo tumor models, AOM/DSS mouse model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue, in vivo model, single lab","pmids":["34109174"],"is_preprint":false},{"year":2023,"finding":"BRD7 negatively regulates BIRC2 expression by targeting and inhibiting the activity of the B7BS enhancer region of BIRC2; restoration of BIRC2 rescues the tumor suppressive effects of BRD7 on NPC cell proliferation, migration, invasion, and xenograft tumor growth.","method":"ChIP, luciferase enhancer reporter assay, BIRC2 rescue experiment, in vitro and in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating BRD7 occupancy at BIRC2 enhancer, reporter assay, functional rescue, in vivo model, single lab","pmids":["36788209"],"is_preprint":false},{"year":2024,"finding":"BRD7 bridges BRG1 and PBRM1 to the core module of the PBAF complex during CD8+ T cell activation, facilitating PBAF assembly over BAF; the resulting PBAF complex increases chromatin accessibility at the Tbx21 locus and upregulates T-bet expression, driving maturation of short-lived effector CD8+ T cells.","method":"BRD7 conditional knockout in CD8+ T cells, co-immunoprecipitation, ATAC-seq (chromatin accessibility), flow cytometry, viral infection models (influenza, LCMV)","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic KO with mechanistic Co-IP, chromatin accessibility (ATAC-seq), and in vivo functional readouts, multiple orthogonal methods","pmids":["38954484"],"is_preprint":false},{"year":2023,"finding":"BRD7 competitively inhibits binding of the deubiquitinase USP5 to METTL3, reducing METTL3 protein stability via the ubiquitin-proteasome pathway; this suppresses BRCA1- and RAD51-mediated homologous recombination repair, increasing radiosensitivity of NPC cells.","method":"Co-immunoprecipitation, competitive binding assay (BRD7 vs USP5 for METTL3), ubiquitination assay, DNA damage (DSB) assays, homologous recombination repair assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with competitive binding, ubiquitination assay, functional HR repair readout, single lab with multiple orthogonal methods","pmids":["39664566"],"is_preprint":false},{"year":2024,"finding":"BRD7 directly binds EZH2 and recruits DNMT3a to the Clusterin promoter, modulating Clusterin promoter hypermethylation; reduced Clusterin expression suppresses AMPK signaling to facilitate ferroptosis in diabetic testicular damage.","method":"Co-immunoprecipitation (BRD7-EZH2, BRD7-DNMT3a), methylation-specific PCR, ChIP assay, BRD7 knockdown, Clusterin rescue experiment","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, MSP with functional rescue, single lab with multiple orthogonal methods","pmids":["38992588"],"is_preprint":false},{"year":2023,"finding":"BRD7 silencing stabilizes CHK1 (but not CHK2) by increasing USP1 levels and promoting the CHK1-USP1 interaction, enhancing CHK1 deubiquitination; USP1 knockdown abrogates BRD7 silencing-induced CHK1 induction, establishing BRD7 as a negative regulator of CHK1 through the USP1 deubiquitinase axis.","method":"BRD7 siRNA, CHK1/CHK2 western blot, co-immunoprecipitation (CHK1-USP1), ubiquitination assay, USP1 knockdown rescue, apoptosis assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic rescue with USP1 KD, single lab with multiple orthogonal methods","pmids":["37626049"],"is_preprint":false},{"year":2011,"finding":"miR-200c directly inhibits BRD7 expression; BRD7 loss induced by miR-200c leads to β-catenin nuclear translocation and increased expression of cyclin D1 and c-Myc in endometrial carcinoma cells.","method":"miRNA transfection, mRNA microarray, western blot, β-catenin localization assay","journal":"Gynecologic oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect (miRNA-mediated BRD7 depletion), single lab, β-catenin localization but no direct BRD7 binding/mechanism experiment","pmids":["22015043"],"is_preprint":false},{"year":2016,"finding":"BRD7 acts as a transcription factor to up-regulate the expression of miR-3148 at the transcriptional level; miR-3148 then targets the 3'UTR of Wnt3a mRNA to suppress Wnt3a/β-catenin signaling in cervical cancer cells.","method":"BRD7 overexpression, luciferase reporter assay for miR-3148 promoter activity, 3'UTR luciferase assay for Wnt3a targeting, western blot","journal":"Reproductive sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter assay for BRD7-driven transcription of miR-3148, single lab with limited mechanistic depth for BRD7's direct action","pmids":["32046432"],"is_preprint":false},{"year":2023,"finding":"BRD7 interacts with InsR (insulin receptor) as shown by co-immunoprecipitation; BRD7 improves glucose homeostasis in liver-specific IRS1/2 double knockout mice, demonstrating that BRD7's effect on insulin signaling operates through an IRS-independent alternative pathway downstream of InsR.","method":"Co-immunoprecipitation (BRD7-InsR), liver-specific InsR KO and IRS1/2 KO mouse models, glucose tolerance and insulin signaling assays","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with genetic KO models and functional metabolic readout, pathway dissection via conditional knockouts, single lab","pmids":["37578842"],"is_preprint":false},{"year":2025,"finding":"Brd7 loss in breast cancer metastatic dormancy models induces metastatic reawakening; Brd7-deficient cells downregulate MHC-1 expression and promote a pro-metastatic cytokine profile, increasing pro-tumorigenic neutrophils, CD8+ exhausted T cells, and CD4+ stress-response T cells in the lung microenvironment; neutrophil depletion, NET inhibition, or immune checkpoint therapy abrogates this metastatic outgrowth.","method":"In vivo PBAF subunit screen, flow cytometry, single-cell RNA-seq, epigenomic profiling, neutrophil depletion, NET inhibition, immune checkpoint therapy","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic screen confirmed by multiple mechanistic approaches including single-cell analysis, epigenomics, and therapeutic rescue experiments","pmids":["39910049"],"is_preprint":false}],"current_model":"BRD7 is a PBAF-specific SWI/SNF chromatin-remodeling complex subunit whose bromodomain binds acetylated histone H3/H4 peptides; it functions as a transcriptional co-regulator and tumor suppressor by interacting with p53 (promoting its transcriptional activity and stability via AKT/MDM2 inhibition and facilitating p53 mitochondrial translocation in ferroptosis), BRCA1 (co-regulating a subset of BRCA1 target genes), p85α/β (PI3K regulatory subunits, regulating PI3K/AKT signaling and XBP1s nuclear translocation), and multiple E3/deubiquitinase systems (PARP1/RNF146-mediated PARylation-dependent degradation, TRIM28- and TRIM25-mediated ubiquitination at K21/K119, and APC/C-Cdh1/Cdc20-mediated cell-cycle degradation); it is negatively regulated by c-Myc at the transcriptional level and by promoter methylation; in DNA damage response, ATM-phosphorylated BRD7 recruits PRC2, NuRD, and RNF168 to DSBs to couple transcriptional repression with repair; in immune contexts, BRD7 bridges the PBAF complex assembly to drive CD8+ T cell effector differentiation and restrains metastatic dormancy release by maintaining immunosurveillance."},"narrative":{"mechanistic_narrative":"BRD7 is a bromodomain-containing subunit of the PBAF-specific SWI/SNF chromatin-remodeling complex that acts as a transcriptional co-regulator and tumor suppressor by coupling acetylated-chromatin recognition to the activity of sequence-specific regulators [PMID:18809673, PMID:16265664]. Its bromodomain adopts a four-helix bundle that binds acetylated lysines on histone H3 and H4 (H3K9ac, H3K14ac, H4K8/12/16ac), an interaction required for its transcriptional control of cell-cycle genes such as E2F3 and for G1-S arrest [PMID:16265664, PMID:17498659]; nuclear function depends on a bipartite NLS, and loss of nuclear localization abolishes cell-cycle regulation [PMID:16475162]. BRD7 physically interacts with p53 and p300, is recruited to p53 target promoters, and is required for efficient p53-dependent transcription and oncogene-induced senescence [PMID:20228809, PMID:20660729]; it further stabilizes p53 by blocking AKT-dependent MDM2 phosphorylation and p53 ubiquitination through its bromodomain [PMID:35371302], and under ferroptotic conditions binds the p53 transactivation domain to drive p53 mitochondrial translocation and SLC25A28-dependent iron accumulation [PMID:32863216]. It also directly binds BRCA1 to co-regulate a subset of target genes including ESR1/ERα [PMID:20215511] and engages the PI3K regulatory subunits p85α/β, competing with p110 and driving nuclear translocation of p85 and XBP1s to restrain PI3K/AKT signaling and support the unfolded protein response and glucose homeostasis [PMID:24657164, PMID:24836559]. In the DNA damage response, ATM-phosphorylated BRD7 is recruited to double-strand breaks where it joins PRC2 and NuRD and recruits RNF168 to couple local transcriptional repression with repair [PMID:33101843]. BRD7 protein levels are controlled by multiple ubiquitin-dependent routes, including PARP1/RNF146 PARylation-coupled degradation [PMID:30940648], TRIM28- and TRIM25-mediated K48 ubiquitination at K21 and K119 [PMID:39222175, PMID:41315221], and APC/C-Cdh1/Cdc20 cell-cycle degradation [PMID:24840027]. In immunity, BRD7 bridges BRG1 and PBRM1 to nucleate PBAF assembly, increasing chromatin accessibility at Tbx21 to drive CD8+ T cell effector differentiation [PMID:38954484], and maintains metastatic dormancy by sustaining MHC-1 expression and tumor immunosurveillance [PMID:39910049].","teleology":[{"year":2000,"claim":"Early interaction screens placed BRD7 in the nucleus in association with transcriptional regulators, establishing it as a candidate chromatin-associated co-regulator before its complex membership was known.","evidence":"Yeast two-hybrid and GST pull-down with IRF-2, plus PTP-BL PDZ-domain interaction, with immunofluorescence showing nuclear co-localization with active chromatin marks","pmids":["11025449","10526152"],"confidence":"Low","gaps":["Functional consequence of the IRF-2 and PTP-BL interactions not established","No demonstration of a chromatin-remodeling role at this stage"]},{"year":2003,"claim":"BRD7 was shown to modulate transcription through partner proteins and direct histone contact, framing it as a bromodomain reader that tunes activator/repressor balance.","evidence":"Co-IP, GST pull-down and reporter assays with E1B-AP5/hnRNP and Dvl-1, including a BRD7-histone triple complex and Wnt/β-catenin readouts","pmids":["12489984","12941796"],"confidence":"High","gaps":["Specificity of histone-mark recognition not resolved","Mechanism linking BRD7 to β-catenin nuclear translocation incompletely defined"]},{"year":2006,"claim":"The bromodomain and an NLS were defined as the molecular determinants of BRD7 chromatin function and cell-cycle control, answering how BRD7 engages chromatin to regulate proliferation.","evidence":"Histone peptide pull-down with bromodomain-deletion mutant, GFP-NLS deletion constructs, reporter assays and flow cytometry on E2F3/cyclin D1 and G1-S progression","pmids":["16265664","16475162"],"confidence":"Medium","gaps":["In vitro mark preference not yet structurally explained","Single-lab functional readouts"]},{"year":2007,"claim":"A structural model of the BRD7 bromodomain explained its acetyl-lysine reader fold while revealing low intrinsic mark selectivity, implying targeting specificity arises from complex context.","evidence":"NMR structure determination and titration with H3/H4 acetyl-lysine peptides","pmids":["17498659"],"confidence":"High","gaps":["Does not address in-vivo mark selectivity within PBAF","No co-structure with histone or other subunits"]},{"year":2008,"claim":"BRD7 was defined biochemically as a PBAF-specific SWI/SNF subunit, distinguishing it from BAF and establishing its remodeling-complex identity.","evidence":"MS-based complex purification, shRNA knockdown of BRD7 vs ARID1A, gene-expression profiling and PIC recruitment assays; also BRD2 and Ceap-16/BLOS2 interactions mapped","pmids":["18809673","16786191","18329849"],"confidence":"High","gaps":["How BRD7 directs PBAF to specific loci not fully defined","Functional roles of BRD2 and Ceap-16 interactions underexplored"]},{"year":2010,"claim":"BRD7 was established as a required co-regulator for p53 and BRCA1 transcriptional programs, defining its tumor-suppressor function at target promoters.","evidence":"Reciprocal Co-IP, ChIP, reporter and senescence assays for p53/p300; yeast two-hybrid and endogenous Co-IP with BRCA1, ESR1 promoter ChIP","pmids":["20228809","20660729","20215511"],"confidence":"High","gaps":["Which target subsets require BRD7 versus the broader PBAF complex unclear","Direct versus complex-mediated recruitment not fully separated"]},{"year":2014,"claim":"BRD7 was shown to restrain PI3K/AKT signaling and regulate the UPR by sequestering and relocalizing p85 subunits, extending its role beyond chromatin to cytoplasmic signaling and metabolism.","evidence":"Co-IP with domain mapping, RNAi, AKT phosphorylation and fractionation assays for p85α; in vivo adenoviral BRD7 rescue in obese mice with XBP1s nuclear translocation and glucose readouts; APC/C-mediated degradation defined","pmids":["24657164","24836559","24840027"],"confidence":"High","gaps":["Balance between nuclear chromatin and cytoplasmic p85-sequestering functions unresolved","How metabolic and tumor-suppressor roles are coordinated unclear"]},{"year":2019,"claim":"BRD7 stability was shown to be controlled by PARylation-coupled ubiquitination, explaining how chemotherapy-induced DNA damage lowers BRD7 levels.","evidence":"Co-IP, PARylation and ubiquitination assays, RNF146 knockdown and protein-stability western blots","pmids":["30940648"],"confidence":"High","gaps":["Functional consequence of BRD7 loss for chemoresponse not fully defined here","Other PAR-dependent ligases not excluded"]},{"year":2020,"claim":"BRD7 was integrated into the DNA damage response and into protein-stability control of metastasis drivers, broadening its mechanistic reach in cancer.","evidence":"ATM-phosphorylation mapping and Co-IP with PRC2/NuRD/RNF168 at DSBs; ferroptosis Co-IP with p53 TAD and SLC25A28; YB1 phospho-degradation and metastasis assays; HIF1α degradation and glycolysis assays","pmids":["33101843","32863216","32028981","29725006"],"confidence":"High","gaps":["Hierarchy among these many BRD7 protein-stability targets unclear","Cell-type specificity of each axis not systematically compared"]},{"year":2024,"claim":"BRD7 was defined as the bridging factor that nucleates PBAF assembly during CD8+ T cell activation, connecting its chromatin-remodeling role to adaptive immunity.","evidence":"Conditional CD8+ T cell knockout, Co-IP of BRG1/PBRM1, ATAC-seq at Tbx21, and viral infection models; TRIM28 K21 ubiquitination also defined","pmids":["38954484","39222175"],"confidence":"High","gaps":["How BRD7-driven PBAF selection generalizes beyond the Tbx21 locus unknown","Relationship between immune and tumor-suppressor functions undefined"]},{"year":2025,"claim":"BRD7 was identified as a restraint on metastatic dormancy release through maintenance of MHC-1 and tumor immunosurveillance, linking its PBAF function to anti-metastatic immunity.","evidence":"In vivo PBAF subunit screen with single-cell RNA-seq, epigenomic profiling, neutrophil depletion, NET inhibition and immune checkpoint therapy; TRIM25 K119 ubiquitination axis defined","pmids":["39910049","41315221"],"confidence":"High","gaps":["Direct chromatin targets controlling MHC-1 not pinpointed","Whether the immune phenotype is cell-intrinsic or microenvironment-driven not fully separated"]},{"year":null,"claim":"It remains unknown how BRD7's locus-specific PBAF targeting, its many cytoplasmic protein-stability functions, and its tissue-specific phenotypes are mechanistically unified under a single regulatory logic.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of BRD7 within assembled PBAF on chromatin","No integrated model reconciling nuclear chromatin versus cytoplasmic signaling roles","Genome-wide direct BRD7 binding map not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,13,31]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,4,8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2,31]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,32]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,29]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,9,10]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,1,17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[17,33]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,13,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,25]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[32,39]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14,27,28]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[16,1]}],"complexes":["PBAF (PBAF-specific SWI/SNF complex)"],"partners":["TP53","BRCA1","PIK3R1","EZH2","BRG1","PBRM1","HIF1A","YBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPI1","full_name":"Bromodomain-containing protein 7","aliases":["75 kDa bromodomain protein","Protein CELTIX-1"],"length_aa":651,"mass_kda":74.1,"function":"Acts both as coactivator and as corepressor. May play a role in chromatin remodeling. Activator of the Wnt signaling pathway in a DVL1-dependent manner by negatively regulating the GSK3B phosphotransferase activity. Induces dephosphorylation of GSK3B at 'Tyr-216'. Down-regulates TRIM24-mediated activation of transcriptional activation by AR (By similarity). Transcriptional corepressor that down-regulates the expression of target genes. Binds to target promoters, leading to increased histone H3 acetylation at 'Lys-9' (H3K9ac). Binds to the ESR1 promoter. Recruits BRCA1 and POU2F1 to the ESR1 promoter. Coactivator for TP53-mediated activation of transcription of a set of target genes. Required for TP53-mediated cell-cycle arrest in response to oncogene activation. Promotes acetylation of TP53 at 'Lys-382', and thereby promotes efficient recruitment of TP53 to target promoters. Inhibits cell cycle progression from G1 to S phase","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NPI1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BRD7","classification":"Not Classified","n_dependent_lines":257,"n_total_lines":1208,"dependency_fraction":0.21274834437086093},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PHF10","stoichiometry":10.0},{"gene":"SMARCA4","stoichiometry":4.0},{"gene":"SMARCC2","stoichiometry":4.0},{"gene":"SMARCD1","stoichiometry":4.0},{"gene":"SMARCD2","stoichiometry":4.0},{"gene":"H1F0","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BRD7","total_profiled":1310},"omim":[{"mim_id":"618489","title":"BROMODOMAIN-CONTAINING PROTEIN 7; BRD7","url":"https://www.omim.org/entry/618489"},{"mim_id":"616888","title":"TRANSMEMBRANE PROTEIN 8B; TMEM8B","url":"https://www.omim.org/entry/616888"},{"mim_id":"606083","title":"POLYBROMO 1; PBRM1","url":"https://www.omim.org/entry/606083"},{"mim_id":"605800","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN U-LIKE 1; HNRNPUL1","url":"https://www.omim.org/entry/605800"},{"mim_id":"603109","title":"SMAD FAMILY MEMBER 3; SMAD3","url":"https://www.omim.org/entry/603109"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BRD7"},"hgnc":{"alias_symbol":["CELTIX1","BP75","SMARCI1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NPI1","domains":[{"cath_id":"1.20.920.10","chopping":"136-254","consensus_level":"high","plddt":93.7574,"start":136,"end":254},{"cath_id":"-","chopping":"393-438","consensus_level":"medium","plddt":83.9315,"start":393,"end":438},{"cath_id":"-","chopping":"538-616","consensus_level":"medium","plddt":87.3662,"start":538,"end":616}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPI1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPI1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPI1-F1-predicted_aligned_error_v6.png","plddt_mean":64.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BRD7","jax_strain_url":"https://www.jax.org/strain/search?query=BRD7"},"sequence":{"accession":"Q9NPI1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPI1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPI1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPI1"}},"corpus_meta":[{"pmid":"30540463","id":"PMC_30540463","title":"Iterative 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Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12600283","citation_count":8,"is_preprint":false},{"pmid":"22864638","id":"PMC_22864638","title":"No evidence for breast cancer susceptibility associated with variants of BRD7, a component of p53 and BRCA1 pathways.","date":"2012","source":"Familial cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22864638","citation_count":8,"is_preprint":false},{"pmid":"36777828","id":"PMC_36777828","title":"AGAP2-AS1/BRD7/c-Myc signaling axis promotes skin cutaneous melanoma progression.","date":"2023","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/36777828","citation_count":7,"is_preprint":false},{"pmid":"34751372","id":"PMC_34751372","title":"The regulatory subunits of PI3K, p85α and p85β, differentially affect BRD7-mediated regulation of insulin signaling.","date":"2022","source":"Journal of molecular cell 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Series C, Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18759043","citation_count":5,"is_preprint":false},{"pmid":"34470615","id":"PMC_34470615","title":"Is BRD7 associated with spermatogenesis impairment and male infertility in humans? A case-control study in a Han Chinese population.","date":"2021","source":"Basic and clinical andrology","url":"https://pubmed.ncbi.nlm.nih.gov/34470615","citation_count":4,"is_preprint":false},{"pmid":"37626049","id":"PMC_37626049","title":"BRD7 suppresses tumor chemosensitivity to CHK1 inhibitors by inhibiting USP1-mediated deubiquitination of CHK1.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37626049","citation_count":3,"is_preprint":false},{"pmid":"12526210","id":"PMC_12526210","title":"Analysis of bromodomain of BRD-7 gene and its prokaryotic expression.","date":"2002","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12526210","citation_count":3,"is_preprint":false},{"pmid":"37578842","id":"PMC_37578842","title":"BRD7 improves glucose homeostasis independent of IRS proteins.","date":"2023","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37578842","citation_count":2,"is_preprint":false},{"pmid":"39695102","id":"PMC_39695102","title":"Tumor- and host-derived heparanase-2 (Hpa2) attenuates tumorigenicity: role of Hpa2 in macrophage polarization and BRD7 nuclear localization.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39695102","citation_count":2,"is_preprint":false},{"pmid":"37365429","id":"PMC_37365429","title":"Identification of BRD7 by whole-exome sequencing as a predictor for intermediate-stage hepatocellular carcinoma in patients undergoing TACE.","date":"2023","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37365429","citation_count":2,"is_preprint":false},{"pmid":"31079594","id":"PMC_31079594","title":"Nuclear trafficking dynamics of Bromodomain-containing protein 7 (BRD7), a switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex subunit, in porcine oocytes and cleavage-stage embryos.","date":"2019","source":"Reproduction, fertility, and development","url":"https://pubmed.ncbi.nlm.nih.gov/31079594","citation_count":2,"is_preprint":false},{"pmid":"21873788","id":"PMC_21873788","title":"[Definition and function identification of nucleus export signal of BRD7].","date":"2011","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. 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knockdown of BRD7 (PBAF-specific) and ARID1A (BAF-specific) differentially and sometimes antagonistically regulate SWI/SNF target genes, and SWI/SNF affects recruitment of preinitiation complex components at target promoters.\",\n      \"method\": \"Mass spectrometry-based complex purification, shRNA knockdown, gene expression profiling, preinitiation complex recruitment assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical complex identification by MS, functional validation by shRNA with defined transcriptional readouts, replicated in ESCs and differentiated cells\",\n      \"pmids\": [\"18809673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BRD7 physically interacts with p53 and p300, is recruited to p53 target gene promoters, and is required for efficient p53-mediated transcription of a subset of target genes; BRD7 affects histone acetylation and p53 acetylation at these promoters, supporting oncogene-induced senescence.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, luciferase reporter assays, senescence assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with p53 and p300, ChIP showing promoter recruitment, functional senescence readout, replicated in multiple cell lines\",\n      \"pmids\": [\"20228809\", \"20660729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BRD7 directly binds BRCA1 (identified by yeast two-hybrid, confirmed by co-immunoprecipitation of endogenous proteins), and is required for BRCA1-mediated transcriptional regulation; BRD7 depletion prevents recruitment of BRCA1 and Oct-1 to the ESR1 promoter, reducing ERα expression, without affecting recruitment of other SWI/SNF subunits (BRG1, BAF155, BAF57) or RNA Pol II.\",\n      \"method\": \"Yeast two-hybrid, endogenous co-immunoprecipitation, ChIP, microarray expression profiling, shRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid confirmed by endogenous Co-IP, ChIP showing promoter occupancy, specific mechanistic distinction from other SWI/SNF subunits\",\n      \"pmids\": [\"20215511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BRD7's bromodomain binds acetylated histone H3 (specifically H3K14ac), co-localizes with acetylated H3 in the nucleus, and this interaction is required for BRD7-mediated transcriptional regulation of E2F3 and inhibition of G1-S cell cycle progression; a bromodomain-deleted BRD7 mutant fails to bind acetylated H3 peptide and loses these functions.\",\n      \"method\": \"Co-localization immunofluorescence, histone peptide pull-down, bromodomain deletion mutant analysis, luciferase reporter assay, flow cytometry\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro peptide binding with mutagenesis, functional validation by reporter assay and cell cycle analysis in single lab\",\n      \"pmids\": [\"16265664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NMR solution structure of the BRD7 bromodomain reveals a typical left-handed four-helix bundle topology; NMR titration experiments show it binds with weak affinity to acetylated lysine peptides from H3 (K9ac, K14ac) and H4 (K8ac, K12ac, K16ac), lacking inherent binding specificity among these marks in vitro.\",\n      \"method\": \"NMR spectroscopy (structure determination and titration)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional binding characterization, single lab but rigorous structural method\",\n      \"pmids\": [\"17498659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BRD7 contains a functional nuclear localization signal (NLS) spanning amino acids 65–96 composed of bipartite nuclear targeting sequences; deletion of the NLS shifts BRD7 localization from nucleus to cytoplasm and abolishes its ability to regulate cyclin D1, E2F3 expression, and G1-S cell cycle progression.\",\n      \"method\": \"GFP fusion constructs, deletion mutagenesis, fluorescence microscopy, western blot, flow cytometry\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutagenesis with GFP reporters and functional cell cycle readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16475162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRD7 interacts with the inter-SH2 (iSH2) domain of p85α (PI3K regulatory subunit) via a conserved C-terminal region, facilitates nuclear translocation of p85α, depletes cytosolic p85/p110 complexes, and thereby reduces p110 protein stability and PI3K/Akt pathway signaling; BRD7 and p110 compete for binding to p85.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, RNAi knockdown, Akt phosphorylation assays, subcellular fractionation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, RNAi gain/loss of function, mechanistic competition model validated by multiple biochemical approaches\",\n      \"pmids\": [\"24657164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRD7 interacts with regulatory subunits of PI3K (p85α and p85β) and promotes nuclear translocation of both p85 isoforms and the spliced form of XBP1 (XBP1s); BRD7 deficiency blocks nuclear translocation of XBP1s, impairing the unfolded protein response (UPR); restoring hepatic BRD7 in obese mice improves XBP1s nuclear translocation and glucose homeostasis.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, in vivo mouse models (adenoviral BRD7 restoration), glucose tolerance tests\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, subcellular fractionation, and in vivo rescue experiment with functional metabolic readout, replicated across cell lines and mouse models\",\n      \"pmids\": [\"24836559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BRD7 (Celtix-1/BP75) forms a complex with the heterogeneous nuclear ribonucleoprotein E1B-AP5 both in vivo and in vitro; disruption of this complex increases E1B-AP5 transcriptional repression activity and converts E1B-AP5 from an activator to a strong repressor of hormone-dependent promoters; BRD7 bromodomain binds histones H2A, H2B, H3, and H4, and a triple complex of E1B-AP5, BRD7, and histones was demonstrated.\",\n      \"method\": \"Yeast two-hybrid, in vivo and in vitro co-immunoprecipitation, GST pull-down, luciferase reporter assays, deletion mutagenesis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro and in vivo binding confirmed, GST pull-down, functional transcriptional readout with mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12489984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BRD7 (Celtix-1) interacts with IRF-2 via the C-terminus of IRF-2, as established by yeast two-hybrid and GST pull-down; a subset of BRD7/Celtix-1 co-localizes with hyperacetylated histones H3/H4 and the hyperphosphorylated (active) form of RNA Pol II in the nucleus.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, immunofluorescence co-localization\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid confirmed by GST pull-down, immunofluorescence co-localization with active chromatin marks, single lab\",\n      \"pmids\": [\"11025449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BP75 (BRD7) was identified through interaction with the first PDZ domain of protein tyrosine phosphatase PTP-BL in a yeast two-hybrid screen; both BP75 and a PTP-BL PDZ domain construct localize primarily to the nucleus.\",\n      \"method\": \"Yeast two-hybrid, subcellular localization by immunofluorescence\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid identification with localization data, no functional validation of interaction consequence\",\n      \"pmids\": [\"10526152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BP75 (BRD7) directly interacts with Dvl-1 (Dishevelled-1), enhances TCF-dependent gene expression induced by Dvl-1, facilitates dephosphorylation of GSK-3β at Tyr216 thereby inhibiting its kinase activity, and synergizes with Dvl-1 to promote nuclear translocation of β-catenin.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, TCF luciferase reporter assay, GSK-3β kinase assay, β-catenin localization\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in mammalian cells, functional reporter and kinase activity assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12941796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BRD7 interacts with TRIM24/TIF1α and represses TRIM24-enhanced androgen receptor (AR) transactivation activity, as measured by luciferase reporter assay in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and reporter assay, single lab, no domain mapping or rescue experiment\",\n      \"pmids\": [\"19909775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ectopic BRD7 expression in NPC cells inhibits G1-S progression and transcriptionally regulates molecules in the Ras/MEK/ERK and Rb/E2F pathways; BRD7 negatively regulates E2F3 promoter activity.\",\n      \"method\": \"Tet-on inducible expression, cell cycle cDNA array, luciferase reporter assay, flow cytometry\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system with cell cycle array and promoter reporter assay, multiple readouts in single lab\",\n      \"pmids\": [\"15137061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PARP-1 binds to BRD7 and poly(ADP-ribosyl)ates it; this modification enhances BRD7 ubiquitination and degradation through the PAR-binding E3 ubiquitin ligase RNF146, leading to BRD7 degradation in response to DNA damage-inducing chemotherapy.\",\n      \"method\": \"Co-immunoprecipitation, PAR assay (PARylation), ubiquitination assay, RNF146 knockdown, western blot for protein stability\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, direct PARylation assay, ubiquitination assay, genetic knockdown of E3 ligase, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"30940648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRD7 forms a complex with the APC/C (anaphase-promoting complex/cyclosome) and is degraded by APC/C(Cdh1) and APC/C(Cdc20) during the cell cycle; a BRD7 mutant resistant to APC/C-mediated degradation more efficiently suppresses osteosarcoma proliferation and tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, APC/C inhibitor (proTAME), APC/C degradation-resistant mutant, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with APC/C, functional mutant validation, in vivo tumor model, single lab\",\n      \"pmids\": [\"24840027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRD7 expression is increased by inhibition of the ubiquitin-proteasome pathway upon ferroptosis induction; elevated BRD7 promotes p53 mitochondrial translocation via direct binding to the p53 N-terminal transactivation domain (TAD); site-directed mutation of p53 serine 392 blocks BRD7-p53 binding and prevents p53 mitochondrial translocation and ferroptosis; mitochondrial p53 then interacts with SLC25A28 to enhance its activity, leading to iron accumulation and ferroptosis.\",\n      \"method\": \"CRISPR/Cas9 knockout, BRD7 overexpression plasmid, co-immunoprecipitation, site-directed mutagenesis, subcellular fractionation, SLC25A28 knockdown\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mutagenesis, CRISPR KO and OE with mechanistic rescue, subcellular fractionation, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"32863216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRD7 is recruited to DNA double-strand break (DSB) sites via ATM-mediated phosphorylation; at DSBs, BRD7 joins PRC2 and NuRD complexes and recruits E3 ubiquitin ligase RNF168, leading to transcriptional repression at active transcription sites flanking DSBs and facilitating DNA repair.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, immunofluorescence, ATM inhibitor treatment, phosphorylation site mapping, RNF168 recruitment assay, DNA repair assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with PRC2/NuRD/RNF168, ChIP, ATM phosphorylation mapping, functional DSB repair assays, multiple orthogonal methods\",\n      \"pmids\": [\"33101843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRD7 interacts with YB1 via its N-terminus binding to the C-terminus of YB1; BRD7 decreases YB1 expression by negatively regulating YB1 phosphorylation at Ser102, promoting its proteasomal degradation, thereby suppressing YB1-induced epithelial-mesenchymal transition (EMT), invasion, and metastasis in breast cancer.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, deletion mutant mapping, phosphorylation assay, ubiquitination/proteasome assay, in vitro migration/invasion assays, xenograft and metastatic mouse models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identification, reciprocal Co-IP domain mapping, phosphorylation and proteasome assays, in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"32028981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BRD7 interacts with BRD2 (co-immunoprecipitation confirmed in mammalian cells); the region from amino acids 430–798 of BRD2 is critical for this interaction; BRD2 localizes in the nucleus in diffuse and dotted patterns.\",\n      \"method\": \"Co-immunoprecipitation, GFP fluorescence, deletion mutant analysis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with domain mapping, limited functional follow-up on interaction consequence\",\n      \"pmids\": [\"16786191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The centrosome-associated protein Ceap-16/BLOS2 directly interacts with BRD7 via BRD7's C-terminus and Ceap-16's central region; this interaction translocates Ceap-16 from cytoplasm to nucleus, where it selectively inhibits BRD7's transcriptional suppression of target genes (E2F3, cyclin A); a triple complex of Ceap-16, BRD7, and histones H3/H4 was demonstrated.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), domain mapping, reporter assays, localization studies\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro Co-IP with domain mapping, triple complex demonstrated, functional transcriptional readout, single lab\",\n      \"pmids\": [\"18329849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRD7 knockout mice display an anti-inflammatory phenotype deficiency: BRD7-deficient MEF cells show increased NF-κB (p65) cytoplasm-to-nucleus translocation and elevated inflammatory cytokine expression (IL-6, TNF-α, CXCL-1, iNOS) after LPS stimulation; in vivo, BRD7 KO mice show increased susceptibility to DSS-induced colitis with higher NF-κB nuclear translocation, indicating BRD7 inhibits NF-κB activation during early acute inflammation.\",\n      \"method\": \"BRD7 knockout mouse model, MEF cells, LPS stimulation, NF-κB reporter assay, subcellular fractionation, DSS-induced colitis model\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vitro and in vivo models, NF-κB reporter and fractionation, multiple readouts, single lab\",\n      \"pmids\": [\"27374794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Homozygous BRD7 knockout results in complete male infertility with spermatogenesis arrest at step 13, deformed acrosomal formation, degenerative elongating spermatids, increased apoptosis (TUNEL, annexin V, p53), and elevated DNA damage marker γH2AX; BRD7 is highly expressed in testis and localized to germ cells from pachytene to round spermatid stage.\",\n      \"method\": \"BRD7 knockout mouse model, histology, TUNEL assay, western blot for apoptosis/DNA damage markers, immunohistochemistry\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined histological and molecular phenotype, multiple readouts, single lab\",\n      \"pmids\": [\"26878912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BRD7 knockout impairs cognitive behavior (but not emotional behavior) and reduces synaptic plasticity-related protein expression, neuronal spine density, and dendritic branching specifically in the medial prefrontal cortex (not hippocampus).\",\n      \"method\": \"BRD7 knockout mouse model, behavioral battery tests, western blot for synaptic proteins, neuronal morphology analysis\",\n      \"journal\": \"Behavioural brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with behavioral phenotype and molecular/morphological readouts, region-specific effect validated, single lab\",\n      \"pmids\": [\"25721744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRD7 deficiency leads to embryonic lethality in homozygous knockout mice at mid-gestation (prior to E16.5), establishing an essential developmental role; heterozygous knockdown causes mild changes in glucose metabolism.\",\n      \"method\": \"Homozygous and heterozygous BRD7 knockout mouse models, embryo developmental staging, glucose metabolism assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with clear developmental lethal phenotype and metabolic readouts, single lab\",\n      \"pmids\": [\"27444544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRD7 increases phosphorylation of GSK3β at Ser9 in response to insulin, with this effect occurring even in the absence of AKT activity; BRD7 also mediates phosphorylation of S6K and downstream 4E-BP1; liver-specific BRD7 knockout mice show impaired mTORC1 activity on its downstream targets.\",\n      \"method\": \"BRD7 overexpression, AKT inhibitor, liver-specific BRD7 KO mice, phosphorylation assays (western blot), in vitro and in vivo models\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and OE with mechanistic dissection of pathway, AKT inhibitor experiment, single lab\",\n      \"pmids\": [\"29127434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BRD7 directly interacts with HIF1α and facilitates its degradation via the ubiquitin-proteasome pathway; this reduces LDHA expression and aerobic glycolysis (Warburg effect) in breast cancer cells; bromodomain of BRD7 is required for this activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, bromodomain deletion mutant, LDHA rescue experiment, glycolysis assays, in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, bromodomain mutant, functional rescue, in vivo validation, single lab\",\n      \"pmids\": [\"29725006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM28 acts as an E3 ubiquitin ligase for BRD7; the Coiled-Coil region of TRIM28 binds the N-terminal region of BRD7, mediating K48-linked ubiquitination of BRD7 at K21, leading to proteasomal degradation of BRD7 and promoting breast cancer progression.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, domain mapping, ubiquitination assay (K48 linkage), site-directed mutagenesis (K21), protein stability assay, in vitro and in vivo cancer models\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS, domain mapping, K48-specific ubiquitination and K21 site mutagenesis, in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"39222175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM25 acts as an E3 ubiquitin ligase for BRD7; the PRYSPRY region of TRIM25 binds the N-terminal region of BRD7, increasing K48-linked ubiquitination at K119 and promoting BRD7 proteasomal degradation; this leads to activation of YB1/Bcl-2 signaling, promoting breast cancer malignant progression and paclitaxel resistance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linked, K119 site), domain mapping, protein stability assay, rescue experiment with BRD7 restoration, in vitro and in vivo models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, K48-ubiquitin and K119 site specificity, functional rescue assays, single lab\",\n      \"pmids\": [\"41315221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BRD7 stabilizes p53 protein by inhibiting AKT-dependent phosphorylation of MDM2 (via the BRD7 bromodomain), thereby reducing phospho-MDM2 binding to p53 and decreasing p53 ubiquitination; this mechanism requires the BRD7 bromodomain.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, ubiquitination assay, bromodomain deletion mutant, AKT inhibition, p53 knockdown rescue, in vivo xenograft\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with bromodomain mutant, phosphorylation and ubiquitination assays, mechanistic rescue, single lab\",\n      \"pmids\": [\"35371302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In colorectal cancer, BRD7 interacts with c-Myc and stabilizes c-Myc protein by inhibiting its ubiquitin-proteasome-dependent degradation; restoration of c-Myc in BRD7-silenced CRC cells rescues cell proliferation and tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, c-Myc rescue experiment, in vitro and in vivo tumor models, AOM/DSS mouse model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue, in vivo model, single lab\",\n      \"pmids\": [\"34109174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRD7 negatively regulates BIRC2 expression by targeting and inhibiting the activity of the B7BS enhancer region of BIRC2; restoration of BIRC2 rescues the tumor suppressive effects of BRD7 on NPC cell proliferation, migration, invasion, and xenograft tumor growth.\",\n      \"method\": \"ChIP, luciferase enhancer reporter assay, BIRC2 rescue experiment, in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating BRD7 occupancy at BIRC2 enhancer, reporter assay, functional rescue, in vivo model, single lab\",\n      \"pmids\": [\"36788209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRD7 bridges BRG1 and PBRM1 to the core module of the PBAF complex during CD8+ T cell activation, facilitating PBAF assembly over BAF; the resulting PBAF complex increases chromatin accessibility at the Tbx21 locus and upregulates T-bet expression, driving maturation of short-lived effector CD8+ T cells.\",\n      \"method\": \"BRD7 conditional knockout in CD8+ T cells, co-immunoprecipitation, ATAC-seq (chromatin accessibility), flow cytometry, viral infection models (influenza, LCMV)\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic KO with mechanistic Co-IP, chromatin accessibility (ATAC-seq), and in vivo functional readouts, multiple orthogonal methods\",\n      \"pmids\": [\"38954484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRD7 competitively inhibits binding of the deubiquitinase USP5 to METTL3, reducing METTL3 protein stability via the ubiquitin-proteasome pathway; this suppresses BRCA1- and RAD51-mediated homologous recombination repair, increasing radiosensitivity of NPC cells.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assay (BRD7 vs USP5 for METTL3), ubiquitination assay, DNA damage (DSB) assays, homologous recombination repair assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with competitive binding, ubiquitination assay, functional HR repair readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39664566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRD7 directly binds EZH2 and recruits DNMT3a to the Clusterin promoter, modulating Clusterin promoter hypermethylation; reduced Clusterin expression suppresses AMPK signaling to facilitate ferroptosis in diabetic testicular damage.\",\n      \"method\": \"Co-immunoprecipitation (BRD7-EZH2, BRD7-DNMT3a), methylation-specific PCR, ChIP assay, BRD7 knockdown, Clusterin rescue experiment\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, MSP with functional rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38992588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRD7 silencing stabilizes CHK1 (but not CHK2) by increasing USP1 levels and promoting the CHK1-USP1 interaction, enhancing CHK1 deubiquitination; USP1 knockdown abrogates BRD7 silencing-induced CHK1 induction, establishing BRD7 as a negative regulator of CHK1 through the USP1 deubiquitinase axis.\",\n      \"method\": \"BRD7 siRNA, CHK1/CHK2 western blot, co-immunoprecipitation (CHK1-USP1), ubiquitination assay, USP1 knockdown rescue, apoptosis assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic rescue with USP1 KD, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37626049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"miR-200c directly inhibits BRD7 expression; BRD7 loss induced by miR-200c leads to β-catenin nuclear translocation and increased expression of cyclin D1 and c-Myc in endometrial carcinoma cells.\",\n      \"method\": \"miRNA transfection, mRNA microarray, western blot, β-catenin localization assay\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect (miRNA-mediated BRD7 depletion), single lab, β-catenin localization but no direct BRD7 binding/mechanism experiment\",\n      \"pmids\": [\"22015043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRD7 acts as a transcription factor to up-regulate the expression of miR-3148 at the transcriptional level; miR-3148 then targets the 3'UTR of Wnt3a mRNA to suppress Wnt3a/β-catenin signaling in cervical cancer cells.\",\n      \"method\": \"BRD7 overexpression, luciferase reporter assay for miR-3148 promoter activity, 3'UTR luciferase assay for Wnt3a targeting, western blot\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter assay for BRD7-driven transcription of miR-3148, single lab with limited mechanistic depth for BRD7's direct action\",\n      \"pmids\": [\"32046432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRD7 interacts with InsR (insulin receptor) as shown by co-immunoprecipitation; BRD7 improves glucose homeostasis in liver-specific IRS1/2 double knockout mice, demonstrating that BRD7's effect on insulin signaling operates through an IRS-independent alternative pathway downstream of InsR.\",\n      \"method\": \"Co-immunoprecipitation (BRD7-InsR), liver-specific InsR KO and IRS1/2 KO mouse models, glucose tolerance and insulin signaling assays\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with genetic KO models and functional metabolic readout, pathway dissection via conditional knockouts, single lab\",\n      \"pmids\": [\"37578842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Brd7 loss in breast cancer metastatic dormancy models induces metastatic reawakening; Brd7-deficient cells downregulate MHC-1 expression and promote a pro-metastatic cytokine profile, increasing pro-tumorigenic neutrophils, CD8+ exhausted T cells, and CD4+ stress-response T cells in the lung microenvironment; neutrophil depletion, NET inhibition, or immune checkpoint therapy abrogates this metastatic outgrowth.\",\n      \"method\": \"In vivo PBAF subunit screen, flow cytometry, single-cell RNA-seq, epigenomic profiling, neutrophil depletion, NET inhibition, immune checkpoint therapy\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic screen confirmed by multiple mechanistic approaches including single-cell analysis, epigenomics, and therapeutic rescue experiments\",\n      \"pmids\": [\"39910049\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRD7 is a PBAF-specific SWI/SNF chromatin-remodeling complex subunit whose bromodomain binds acetylated histone H3/H4 peptides; it functions as a transcriptional co-regulator and tumor suppressor by interacting with p53 (promoting its transcriptional activity and stability via AKT/MDM2 inhibition and facilitating p53 mitochondrial translocation in ferroptosis), BRCA1 (co-regulating a subset of BRCA1 target genes), p85α/β (PI3K regulatory subunits, regulating PI3K/AKT signaling and XBP1s nuclear translocation), and multiple E3/deubiquitinase systems (PARP1/RNF146-mediated PARylation-dependent degradation, TRIM28- and TRIM25-mediated ubiquitination at K21/K119, and APC/C-Cdh1/Cdc20-mediated cell-cycle degradation); it is negatively regulated by c-Myc at the transcriptional level and by promoter methylation; in DNA damage response, ATM-phosphorylated BRD7 recruits PRC2, NuRD, and RNF168 to DSBs to couple transcriptional repression with repair; in immune contexts, BRD7 bridges the PBAF complex assembly to drive CD8+ T cell effector differentiation and restrains metastatic dormancy release by maintaining immunosurveillance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BRD7 is a bromodomain-containing subunit of the PBAF-specific SWI/SNF chromatin-remodeling complex that acts as a transcriptional co-regulator and tumor suppressor by coupling acetylated-chromatin recognition to the activity of sequence-specific regulators [#0, #3]. Its bromodomain adopts a four-helix bundle that binds acetylated lysines on histone H3 and H4 (H3K9ac, H3K14ac, H4K8/12/16ac), an interaction required for its transcriptional control of cell-cycle genes such as E2F3 and for G1-S arrest [#3, #4]; nuclear function depends on a bipartite NLS, and loss of nuclear localization abolishes cell-cycle regulation [#5]. BRD7 physically interacts with p53 and p300, is recruited to p53 target promoters, and is required for efficient p53-dependent transcription and oncogene-induced senescence [#1]; it further stabilizes p53 by blocking AKT-dependent MDM2 phosphorylation and p53 ubiquitination through its bromodomain [#29], and under ferroptotic conditions binds the p53 transactivation domain to drive p53 mitochondrial translocation and SLC25A28-dependent iron accumulation [#16]. It also directly binds BRCA1 to co-regulate a subset of target genes including ESR1/ERα [#2] and engages the PI3K regulatory subunits p85α/β, competing with p110 and driving nuclear translocation of p85 and XBP1s to restrain PI3K/AKT signaling and support the unfolded protein response and glucose homeostasis [#6, #7]. In the DNA damage response, ATM-phosphorylated BRD7 is recruited to double-strand breaks where it joins PRC2 and NuRD and recruits RNF168 to couple local transcriptional repression with repair [#17]. BRD7 protein levels are controlled by multiple ubiquitin-dependent routes, including PARP1/RNF146 PARylation-coupled degradation [#14], TRIM28- and TRIM25-mediated K48 ubiquitination at K21 and K119 [#27, #28], and APC/C-Cdh1/Cdc20 cell-cycle degradation [#15]. In immunity, BRD7 bridges BRG1 and PBRM1 to nucleate PBAF assembly, increasing chromatin accessibility at Tbx21 to drive CD8+ T cell effector differentiation [#32], and maintains metastatic dormancy by sustaining MHC-1 expression and tumor immunosurveillance [#39].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Early interaction screens placed BRD7 in the nucleus in association with transcriptional regulators, establishing it as a candidate chromatin-associated co-regulator before its complex membership was known.\",\n      \"evidence\": \"Yeast two-hybrid and GST pull-down with IRF-2, plus PTP-BL PDZ-domain interaction, with immunofluorescence showing nuclear co-localization with active chromatin marks\",\n      \"pmids\": [\"11025449\", \"10526152\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional consequence of the IRF-2 and PTP-BL interactions not established\", \"No demonstration of a chromatin-remodeling role at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"BRD7 was shown to modulate transcription through partner proteins and direct histone contact, framing it as a bromodomain reader that tunes activator/repressor balance.\",\n      \"evidence\": \"Co-IP, GST pull-down and reporter assays with E1B-AP5/hnRNP and Dvl-1, including a BRD7-histone triple complex and Wnt/β-catenin readouts\",\n      \"pmids\": [\"12489984\", \"12941796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity of histone-mark recognition not resolved\", \"Mechanism linking BRD7 to β-catenin nuclear translocation incompletely defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The bromodomain and an NLS were defined as the molecular determinants of BRD7 chromatin function and cell-cycle control, answering how BRD7 engages chromatin to regulate proliferation.\",\n      \"evidence\": \"Histone peptide pull-down with bromodomain-deletion mutant, GFP-NLS deletion constructs, reporter assays and flow cytometry on E2F3/cyclin D1 and G1-S progression\",\n      \"pmids\": [\"16265664\", \"16475162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro mark preference not yet structurally explained\", \"Single-lab functional readouts\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A structural model of the BRD7 bromodomain explained its acetyl-lysine reader fold while revealing low intrinsic mark selectivity, implying targeting specificity arises from complex context.\",\n      \"evidence\": \"NMR structure determination and titration with H3/H4 acetyl-lysine peptides\",\n      \"pmids\": [\"17498659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address in-vivo mark selectivity within PBAF\", \"No co-structure with histone or other subunits\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"BRD7 was defined biochemically as a PBAF-specific SWI/SNF subunit, distinguishing it from BAF and establishing its remodeling-complex identity.\",\n      \"evidence\": \"MS-based complex purification, shRNA knockdown of BRD7 vs ARID1A, gene-expression profiling and PIC recruitment assays; also BRD2 and Ceap-16/BLOS2 interactions mapped\",\n      \"pmids\": [\"18809673\", \"16786191\", \"18329849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BRD7 directs PBAF to specific loci not fully defined\", \"Functional roles of BRD2 and Ceap-16 interactions underexplored\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"BRD7 was established as a required co-regulator for p53 and BRCA1 transcriptional programs, defining its tumor-suppressor function at target promoters.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, reporter and senescence assays for p53/p300; yeast two-hybrid and endogenous Co-IP with BRCA1, ESR1 promoter ChIP\",\n      \"pmids\": [\"20228809\", \"20660729\", \"20215511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which target subsets require BRD7 versus the broader PBAF complex unclear\", \"Direct versus complex-mediated recruitment not fully separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"BRD7 was shown to restrain PI3K/AKT signaling and regulate the UPR by sequestering and relocalizing p85 subunits, extending its role beyond chromatin to cytoplasmic signaling and metabolism.\",\n      \"evidence\": \"Co-IP with domain mapping, RNAi, AKT phosphorylation and fractionation assays for p85α; in vivo adenoviral BRD7 rescue in obese mice with XBP1s nuclear translocation and glucose readouts; APC/C-mediated degradation defined\",\n      \"pmids\": [\"24657164\", \"24836559\", \"24840027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Balance between nuclear chromatin and cytoplasmic p85-sequestering functions unresolved\", \"How metabolic and tumor-suppressor roles are coordinated unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"BRD7 stability was shown to be controlled by PARylation-coupled ubiquitination, explaining how chemotherapy-induced DNA damage lowers BRD7 levels.\",\n      \"evidence\": \"Co-IP, PARylation and ubiquitination assays, RNF146 knockdown and protein-stability western blots\",\n      \"pmids\": [\"30940648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of BRD7 loss for chemoresponse not fully defined here\", \"Other PAR-dependent ligases not excluded\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"BRD7 was integrated into the DNA damage response and into protein-stability control of metastasis drivers, broadening its mechanistic reach in cancer.\",\n      \"evidence\": \"ATM-phosphorylation mapping and Co-IP with PRC2/NuRD/RNF168 at DSBs; ferroptosis Co-IP with p53 TAD and SLC25A28; YB1 phospho-degradation and metastasis assays; HIF1α degradation and glycolysis assays\",\n      \"pmids\": [\"33101843\", \"32863216\", \"32028981\", \"29725006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among these many BRD7 protein-stability targets unclear\", \"Cell-type specificity of each axis not systematically compared\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"BRD7 was defined as the bridging factor that nucleates PBAF assembly during CD8+ T cell activation, connecting its chromatin-remodeling role to adaptive immunity.\",\n      \"evidence\": \"Conditional CD8+ T cell knockout, Co-IP of BRG1/PBRM1, ATAC-seq at Tbx21, and viral infection models; TRIM28 K21 ubiquitination also defined\",\n      \"pmids\": [\"38954484\", \"39222175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BRD7-driven PBAF selection generalizes beyond the Tbx21 locus unknown\", \"Relationship between immune and tumor-suppressor functions undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"BRD7 was identified as a restraint on metastatic dormancy release through maintenance of MHC-1 and tumor immunosurveillance, linking its PBAF function to anti-metastatic immunity.\",\n      \"evidence\": \"In vivo PBAF subunit screen with single-cell RNA-seq, epigenomic profiling, neutrophil depletion, NET inhibition and immune checkpoint therapy; TRIM25 K119 ubiquitination axis defined\",\n      \"pmids\": [\"39910049\", \"41315221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin targets controlling MHC-1 not pinpointed\", \"Whether the immune phenotype is cell-intrinsic or microenvironment-driven not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how BRD7's locus-specific PBAF targeting, its many cytoplasmic protein-stability functions, and its tissue-specific phenotypes are mechanistically unified under a single regulatory logic.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of BRD7 within assembled PBAF on chromatin\", \"No integrated model reconciling nuclear chromatin versus cytoplasmic signaling roles\", \"Genome-wide direct BRD7 binding map not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 13, 31]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2, 31]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 32]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 9, 10]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 1, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [17, 33]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 13, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [32, 39]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14, 27, 28]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [16, 1]}\n    ],\n    \"complexes\": [\"PBAF (PBAF-specific SWI/SNF complex)\"],\n    \"partners\": [\"TP53\", \"BRCA1\", \"PIK3R1\", \"EZH2\", \"BRG1\", \"PBRM1\", \"HIF1A\", \"YBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}