{"gene":"BABAM2","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":1998,"finding":"BRE was identified as a binding partner of the juxtamembrane domain of the p55 TNF receptor (TNFR1) via yeast two-hybrid screen, confirmed by in vitro biochemical assay with recombinant fusion proteins and co-immunoprecipitation in transfected mammalian cells; overexpression of BRE inhibited TNF-induced NF-κB activation.","method":"Yeast two-hybrid, in vitro pulldown with recombinant proteins, co-immunoprecipitation, NF-κB reporter assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional NF-κB assay, multiple orthogonal methods in one study","pmids":["9737713"],"is_preprint":false},{"year":2004,"finding":"BRE binds to the cytoplasmic domain of Fas (in addition to TNFR1) and confers resistance to apoptosis induced by TNF-α, anti-Fas antibody, and stress stimuli by inhibiting the mitochondrial apoptotic pathway without translocating to the mitochondria or nucleus and without reducing truncated Bid levels; BRE dissociates from TNFR1 (but not Fas) upon receptor ligation and shows increased association with phosphorylated, sumoylated, and ubiquitinated proteins after death receptor stimulation.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, apoptosis assays, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, KD, OE, fractionation) with specific mechanistic readouts","pmids":["15465831"],"is_preprint":false},{"year":2011,"finding":"BRE and NBA1/MERIT40 interact via the C-terminal conserved motif of NBA1 and the C-terminal UEV domain of BRE; this interaction is required for the integrity of both BRCC36-containing DUB complexes (nuclear Abraxas complex and cytoplasmic ABRO1 complex), for cellular resistance to ionizing radiation, and for BRCA1 recruitment to DNA damage sites.","method":"Co-immunoprecipitation, siRNA knockdown, domain mapping, ionizing radiation survival assay, immunofluorescence for BRCA1 foci","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping, functional rescue experiments, replicated in two complexes","pmids":["21282113"],"is_preprint":false},{"year":2007,"finding":"Liver-specific transgenic BRE mice are significantly resistant to Fas-mediated lethal hepatic apoptosis in vivo, confirming BRE's anti-apoptotic function in a whole-animal model; post-transcriptional regulation of BRE level occurs in liver but not in cell lines.","method":"Transgenic mouse model, Fas-induced hepatic apoptosis challenge, immunohistochemistry","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss/gain-of-function with specific phenotypic readout, confirms prior mechanistic findings","pmids":["17704801"],"is_preprint":false},{"year":2018,"finding":"BRE (BRCC45) promotes survival of BRCA2-deficient cells by facilitating deubiquitylation of CDC25A phosphatase through recruitment of the deubiquitylase USP7 to CDC25A in the presence of DNA damage, thereby stabilizing CDC25A and deregulating cell cycle checkpoint control.","method":"Insertional mutagenesis screen, co-immunoprecipitation, ubiquitylation assay, cell viability assay, overexpression and knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical co-IP establishing USP7 recruitment, functional rescue, multiple orthogonal methods","pmids":["29416040"],"is_preprint":false},{"year":2014,"finding":"BRE maintains the cellular protein level of XIAP (the most potent endogenous caspase inhibitor) to mediate its anti-apoptotic function; shRNA-mediated depletion of BRE downregulates XIAP protein and mRNA, sensitizes cells to both extrinsic and intrinsic apoptosis, and reconstitution of BRE restores XIAP levels and apoptotic resistance.","method":"shRNA knockdown, reconstitution, Western blot, apoptosis assays, qRT-PCR","journal":"Apoptosis","confidence":"High","confidence_rationale":"Tier 2 — KD plus reconstitution with specific molecular readout (XIAP), multiple methods","pmids":["24395041"],"is_preprint":false},{"year":2016,"finding":"BRE is required for BRCA1-A complex recruitment to DNA damage sites and for homologous recombination (HR)-dependent DNA repair; BRE-/- fibroblasts show impaired γ-H2AX foci resolution, earlier replicative senescence, and increased DNA damage-induced premature senescence.","method":"BRE knockout mouse fibroblasts, immunofluorescence for γ-H2AX foci and BRCA1 recruitment, SA-β-Gal senescence assay, HR assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — KO model with multiple orthogonal readouts (HR assay, foci resolution, senescence)","pmids":["27001068"],"is_preprint":false},{"year":2016,"finding":"BRE facilitates skeletal muscle regeneration by promoting satellite cell motility and chemotactic migration toward SDF-1α, and protects CXCR4 from SDF-1α-induced degradation; BRE-KO mice show impaired muscle regeneration with fewer Pax7+ satellite cells and reduced myofiber formation.","method":"BRE knockout mouse model, tibialis anterior injury model, time-lapse microscopy, chemotaxis assay, immunofluorescence","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 — KO model with specific readouts; CXCR4 protection is single-lab finding","pmids":["26740569"],"is_preprint":false},{"year":2017,"finding":"BRE promotes osteoblastic differentiation by physically interacting with p53 and promoting Mdm2-mediated p53 ubiquitination and degradation; BRE knockdown leads to increased p53, p21, and Mdm2, and inhibition of p53 rescues the impaired osteogenesis caused by BRE loss.","method":"Co-immunoprecipitation, siRNA knockdown, p53 inhibitor rescue, ubiquitination assay, alkaline phosphatase activity, mineralization assay","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional rescue with p53 inhibitor; single lab","pmids":["28436570"],"is_preprint":false},{"year":2022,"finding":"Babam2 (BRE) negatively regulates osteoclastogenesis by interacting with Hey1 to inhibit Nfatc1 transcription; Babam2 knockdown accelerates osteoclast formation, overexpression blocks it, and Hey1 silencing abolishes Babam2's inhibitory effects; Babam2-transgenic mice show increased bone mass and resistance to LPS-induced bone resorption.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, transgenic mouse model, LPS-induced calvarial bone resorption model, Nfatc1 reporter assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis (Hey1 KD rescues), Co-IP, in vivo transgenic model; single lab","pmids":["35864959"],"is_preprint":false},{"year":2005,"finding":"Blocking BRE expression in Leydig cells (mLTC-1) impairs steroidogenesis specifically at the pregnenolone-to-progesterone conversion step by downregulating 3β-hydroxysteroid dehydrogenase type I (3β-HSDI) mRNA, without affecting cAMP production, StAR, or P450scc expression.","method":"Antisense transfection, steroid hormone measurement by RIA, RT-PCR, cAMP assay","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 — antisense knockdown with specific enzymatic readout; single lab, single method approach","pmids":["15930177"],"is_preprint":false},{"year":2020,"finding":"Loss of Babam2 in mouse embryonic stem cells leads to abnormal G1 phase retention after DNA damage (gamma irradiation or doxorubicin), with degradation of key cell cycle regulators CDC25A and CDK2, prolonged p53 expression, and p53-mediated inhibition of Nanog and G1/S progression, reducing developmental pluripotency.","method":"Babam2 knockout mESCs, flow cytometry cell cycle analysis, Western blot for CDC25A/CDK2/p53/Nanog, gamma irradiation and doxorubicin treatment","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 — KO model with multiple molecular and cellular readouts; single lab","pmids":["33050379"],"is_preprint":false},{"year":2017,"finding":"BRE expression in the chick neural tube regulates neural crest cell (NCC) migration, neurite outgrowth, and indirectly somite development; overexpression of BRE increases HNK-1+ NCC migration and TuJ-1+ neurite outgrowth and affects BMP4 and Shh expression in the neural tube.","method":"In ovo electroporation (overexpression/knockdown), in situ hybridization, immunofluorescence, time-lapse imaging in chick embryo","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 — gain/loss-of-function in vivo with specific cellular readouts; ortholog in avian model","pmids":["25568339"],"is_preprint":false},{"year":2020,"finding":"BRE overexpression activates AKT phosphorylation in esophageal squamous cell carcinoma cells to promote cell cycle progression and apoptotic resistance; AKT pathway inhibition by MK2206 reverses BRE-induced growth and survival effects.","method":"Overexpression, siRNA knockdown, AKT inhibitor (MK2206) treatment, Western blot, cell cycle analysis, xenograft model","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with AKT inhibitor plus in vivo validation; single lab","pmids":["32850455"],"is_preprint":false},{"year":2006,"finding":"BRE knockdown in C2C12 cells reduces prohibitin and p53 expression and increases cell proliferation, while BRE overexpression upregulates p53 and prohibitin and decreases proliferation; differentially expressed proteins upon BRE manipulation include targets/crosstalk partners of NF-κB.","method":"siRNA knockdown, overexpression, comparative 2D proteomics, MALDI-TOF MS, cell proliferation assay","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 3 — proteomics with functional follow-up; single lab","pmids":["16518872"],"is_preprint":false},{"year":2001,"finding":"Human BRE is expressed as multiple mRNA isoforms (at least six) generated by alternative splicing at either end of the gene; isoform alpha(a), encoding canonical BRE with a C-terminal peroxisomal targeting sequence, is the most abundant; BRE isoforms are downregulated in monocytes by LPS stimulation.","method":"RT-PCR, Northern blot, sequence analysis of cDNA isoforms","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — molecular characterization of splice variants with functional inference; single lab","pmids":["11676476"],"is_preprint":false}],"current_model":"BABAM2 (BRE/BRCC45) is a multifunctional adaptor protein that: (1) interacts with TNFR1 and Fas cytoplasmic domains to inhibit death receptor-mediated NF-κB activation and mitochondrial apoptosis; (2) serves as a core structural component of two distinct BRCC36 deubiquitinase complexes (nuclear BRCA1-A and cytoplasmic BRISC) through its UEV domain interaction with NBA1/MERIT40; (3) facilitates homologous recombination-based DNA repair by supporting BRCA1-A complex recruitment to damage sites; (4) stabilizes CDC25A by recruiting USP7 for its deubiquitylation in response to DNA damage; (5) maintains XIAP protein levels to broadly suppress caspase activation; and (6) promotes p53 degradation via Mdm2-mediated ubiquitination and negatively regulates osteoclastogenesis by interacting with Hey1 to suppress Nfatc1 transcription."},"narrative":{"teleology":[{"year":1998,"claim":"Identifying BABAM2 as a TNFR1-interacting protein established its initial link to death receptor signaling and NF-κB suppression.","evidence":"Yeast two-hybrid screen with TNFR1 juxtamembrane domain, confirmed by reciprocal Co-IP and NF-κB reporter assay in mammalian cells","pmids":["9737713"],"confidence":"High","gaps":["Mechanism by which BRE inhibits NF-κB was not defined","No endogenous validation at physiological expression levels"]},{"year":2004,"claim":"Demonstration that BABAM2 also binds Fas and protects against both extrinsic and stress-induced apoptosis via the mitochondrial pathway broadened its role from a single-receptor partner to a general anti-apoptotic adaptor.","evidence":"Co-IP with Fas, siRNA knockdown, subcellular fractionation, and apoptosis assays showing mitochondrial pathway inhibition without BRE translocation","pmids":["15465831"],"confidence":"High","gaps":["Direct mitochondrial target of BRE-mediated protection not identified","Post-translational modification changes on BRE after receptor stimulation not functionally assigned"]},{"year":2007,"claim":"In vivo validation using liver-specific BRE transgenic mice confirmed the anti-apoptotic function is physiologically relevant in Fas-mediated hepatic injury.","evidence":"Transgenic mouse model challenged with Fas agonist, with histological and survival readouts","pmids":["17704801"],"confidence":"High","gaps":["Whether BRE anti-apoptotic function in vivo operates through XIAP or another mechanism was untested"]},{"year":2011,"claim":"Mapping the BRE–NBA1/MERIT40 interaction through the UEV domain established BABAM2 as a core structural subunit required for the integrity of both the nuclear BRCA1-A and cytoplasmic BRISC deubiquitinase complexes.","evidence":"Reciprocal Co-IP with domain truncation mapping, siRNA knockdown disrupting both complexes, IR survival and BRCA1 foci assays","pmids":["21282113"],"confidence":"High","gaps":["Structural basis of UEV–NBA1 interaction not resolved at atomic level","Relative contribution of BRCA1-A versus BRISC to radiation resistance not separated"]},{"year":2014,"claim":"Showing that BRE maintains XIAP protein and mRNA levels identified a specific molecular effector through which BABAM2 confers broad caspase-dependent apoptotic resistance.","evidence":"shRNA knockdown and reconstitution restoring XIAP levels and apoptotic resistance in cultured cells","pmids":["24395041"],"confidence":"High","gaps":["Mechanism by which BRE regulates XIAP mRNA is unknown","Whether XIAP regulation is linked to BRE's death receptor binding is untested"]},{"year":2016,"claim":"BRE knockout fibroblasts established that BABAM2 is required for BRCA1-A complex recruitment to DNA damage sites, homologous recombination efficiency, and prevention of premature senescence.","evidence":"BRE−/− mouse fibroblasts with HR reporter assay, γ-H2AX foci resolution kinetics, and senescence-associated β-galactosidase staining","pmids":["27001068"],"confidence":"High","gaps":["Whether senescence phenotype is entirely HR-dependent or involves additional BRE functions not resolved"]},{"year":2017,"claim":"Discovery that BRE promotes Mdm2-mediated p53 ubiquitination and degradation revealed a mechanism connecting BABAM2 to osteoblast differentiation and cell fate control beyond DNA repair.","evidence":"Co-IP of BRE with p53, ubiquitination assay, siRNA knockdown impairing osteogenesis rescued by p53 inhibitor","pmids":["28436570"],"confidence":"Medium","gaps":["Whether BRE–p53 interaction is direct or bridged through Mdm2 not definitively resolved","Single-lab finding awaiting independent replication"]},{"year":2018,"claim":"Identification of BABAM2 as a recruiter of USP7 deubiquitinase to stabilize CDC25A linked its adaptor function to cell cycle checkpoint deregulation and survival of BRCA2-deficient cells.","evidence":"Insertional mutagenesis screen in BRCA2-deficient cells, Co-IP of BRE–USP7–CDC25A, ubiquitylation assays, knockdown and overexpression","pmids":["29416040"],"confidence":"High","gaps":["Whether BRE-mediated CDC25A stabilization occurs in wild-type DNA damage contexts or is specific to BRCA2 loss not fully tested","Structural basis of USP7 recruitment by BRE unknown"]},{"year":2022,"claim":"Demonstrating that BABAM2 partners with Hey1 to repress Nfatc1 transcription and suppress osteoclastogenesis extended its adaptor role to transcriptional regulation of bone homeostasis.","evidence":"Co-IP of BRE with Hey1, Hey1 knockdown abolishing BRE's inhibitory effect on osteoclasts, transgenic mice with increased bone mass and resistance to LPS-induced bone resorption","pmids":["35864959"],"confidence":"Medium","gaps":["Whether BRE–Hey1 interaction is direct or part of a larger complex is unresolved","Single-lab finding in mouse model"]},{"year":null,"claim":"How BABAM2 coordinates its diverse functions—death receptor signaling, BRCA1-A/BRISC complex integrity, USP7-CDC25A stabilization, XIAP maintenance, and transcriptional co-repression—through a single adaptor remains mechanistically unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length BABAM2 exists","Whether distinct pools of BABAM2 serve different complexes or context-dependent switching occurs is unknown","Relative contribution of each function to organismal phenotypes is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,3,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,13]}],"complexes":["BRCA1-A complex","BRISC complex"],"partners":["BABAM1","BRCC3","USP7","TNFRSF1A","FAS","XIAP","TP53","HEY1"],"other_free_text":[]},"mechanistic_narrative":"BABAM2 (BRE/BRCC45) is a multifunctional adaptor protein that integrates death receptor signaling, DNA damage repair, and cell cycle checkpoint control. It binds the cytoplasmic domains of TNFR1 and Fas to suppress NF-κB activation and mitochondrial apoptosis, in part by maintaining XIAP protein levels [PMID:9737713, PMID:15465831, PMID:24395041, PMID:17704801]. Through its C-terminal UEV domain, BABAM2 interacts with NBA1/MERIT40 and is essential for the structural integrity of two BRCC36 deubiquitinase complexes—the nuclear BRCA1-A complex and the cytoplasmic BRISC complex—thereby supporting homologous recombination-based DNA repair and ionizing radiation resistance [PMID:21282113, PMID:27001068]. BABAM2 also recruits USP7 to deubiquitylate and stabilize CDC25A phosphatase after DNA damage, promotes Mdm2-mediated p53 degradation to facilitate osteoblast differentiation, and negatively regulates osteoclastogenesis by cooperating with Hey1 to repress Nfatc1 transcription [PMID:29416040, PMID:28436570, PMID:35864959]."},"prefetch_data":{"uniprot":{"accession":"Q9NXR7","full_name":"BRISC and BRCA1-A complex member 2","aliases":["BRCA1-A complex subunit BRE","BRCA1/BRCA2-containing complex subunit 45","Brain and reproductive organ-expressed protein"],"length_aa":383,"mass_kda":43.6,"function":"Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX (PubMed:17525341, PubMed:19261746, PubMed:19261748, PubMed:19261749). In the BRCA1-A complex, it acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity and modulating the E3 ubiquitin ligase activity of the BRCA1-BARD1 heterodimer (PubMed:19261748, PubMed:21282113). Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:19214193, PubMed:24075985, PubMed:25283148, PubMed:26195665). Within the BRISC complex, acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity (PubMed:21282113). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). The BRISC complex plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). May play a role in homeostasis or cellular differentiation in cells of neural, epithelial and germline origins. May also act as a death receptor-associated anti-apoptotic protein, which inhibits the mitochondrial apoptotic pathway. May regulate TNF signaling through its interactions with TNFRSF1A; however these effects may be indirect (PubMed:15465831)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NXR7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BABAM2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BABAM2","total_profiled":1310},"omim":[{"mim_id":"610497","title":"BRISC AND BRCA1 A COMPLEX, MEMBER 2; BABAM2","url":"https://www.omim.org/entry/610497"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal gland","ntpm":356.9}],"url":"https://www.proteinatlas.org/search/BABAM2"},"hgnc":{"alias_symbol":["BRCC45","BRCC4"],"prev_symbol":["BRE"]},"alphafold":{"accession":"Q9NXR7","domains":[{"cath_id":"3.10.110","chopping":"2-118","consensus_level":"medium","plddt":91.4169,"start":2,"end":118},{"cath_id":"3.10.110","chopping":"269-379","consensus_level":"high","plddt":95.5804,"start":269,"end":379}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NXR7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NXR7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NXR7-F1-predicted_aligned_error_v6.png","plddt_mean":92.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BABAM2","jax_strain_url":"https://www.jax.org/strain/search?query=BABAM2"},"sequence":{"accession":"Q9NXR7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NXR7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NXR7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NXR7"}},"corpus_meta":[{"pmid":"28333135","id":"PMC_28333135","title":"BRE modulates granulosa cell death to affect ovarian follicle development and atresia in the mouse.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28333135","citation_count":64,"is_preprint":false},{"pmid":"8404855","id":"PMC_8404855","title":"Molecular mechanisms of pattern formation by the BRE enhancer of the Ubx gene.","date":"1993","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8404855","citation_count":63,"is_preprint":false},{"pmid":"21282113","id":"PMC_21282113","title":"NBA1/MERIT40 and BRE interaction is required for the integrity of two distinct deubiquitinating enzyme BRCC36-containing complexes.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21282113","citation_count":62,"is_preprint":false},{"pmid":"27733185","id":"PMC_27733185","title":"Over-expression of the long non-coding RNA HOTTIP inhibits glioma cell growth by BRE.","date":"2016","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/27733185","citation_count":47,"is_preprint":false},{"pmid":"9737713","id":"PMC_9737713","title":"BRE: a modulator of TNF-alpha action.","date":"1998","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/9737713","citation_count":44,"is_preprint":false},{"pmid":"15465831","id":"PMC_15465831","title":"A death receptor-associated anti-apoptotic protein, BRE, inhibits mitochondrial apoptotic pathway.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15465831","citation_count":43,"is_preprint":false},{"pmid":"17704801","id":"PMC_17704801","title":"BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17704801","citation_count":37,"is_preprint":false},{"pmid":"29416040","id":"PMC_29416040","title":"BRE/BRCC45 regulates CDC25A stability by recruiting USP7 in response to DNA damage.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29416040","citation_count":34,"is_preprint":false},{"pmid":"21937695","id":"PMC_21937695","title":"High BRE expression predicts favorable outcome in adult acute myeloid leukemia, in particular among MLL-AF9-positive patients.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21937695","citation_count":25,"is_preprint":false},{"pmid":"16518872","id":"PMC_16518872","title":"Comparative proteomic analysis reveals a function of the novel death receptor-associated protein BRE in the regulation of prohibitin and p53 expression and proliferation.","date":"2006","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/16518872","citation_count":24,"is_preprint":false},{"pmid":"18756325","id":"PMC_18756325","title":"Comparative proteomic analysis reveals differentially expressed proteins regulated by a potential tumor promoter, BRE, in human esophageal carcinoma cells.","date":"2008","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/18756325","citation_count":23,"is_preprint":false},{"pmid":"20861917","id":"PMC_20861917","title":"High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome.","date":"2010","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/20861917","citation_count":22,"is_preprint":false},{"pmid":"16157663","id":"PMC_16157663","title":"New positive regulators of lin-12 activity in Caenorhabditis elegans include the BRE-5/Brainiac glycosphingolipid biosynthesis enzyme.","date":"2005","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16157663","citation_count":22,"is_preprint":false},{"pmid":"7493371","id":"PMC_7493371","title":"High-dose 90Y Mx-diethylenetriaminepentaacetic acid (DTPA)-BrE-3 and autologous hematopoietic stem cell support (AHSCS) for the treatment of advanced breast cancer: a phase I trial.","date":"1995","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7493371","citation_count":22,"is_preprint":false},{"pmid":"28436570","id":"PMC_28436570","title":"Bre Enhances Osteoblastic Differentiation by Promoting the Mdm2-Mediated Degradation of p53.","date":"2017","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/28436570","citation_count":22,"is_preprint":false},{"pmid":"30227111","id":"PMC_30227111","title":"Long non-coding RNA BRE-AS1 represses non-small cell lung cancer cell growth and survival via up-regulating NR4A3.","date":"2018","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/30227111","citation_count":22,"is_preprint":false},{"pmid":"30833361","id":"PMC_30833361","title":"LncRNA BRE-AS1 interacts with miR-145-5p to regulate cancer cell proliferation and apoptosis in prostate carcinoma and has early diagnostic values.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/30833361","citation_count":20,"is_preprint":false},{"pmid":"20035718","id":"PMC_20035718","title":"BRE over-expression promotes growth of hepatocellular carcinoma.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20035718","citation_count":19,"is_preprint":false},{"pmid":"23935848","id":"PMC_23935848","title":"Silencing BRE expression in human umbilical cord perivascular (HUCPV) progenitor cells accelerates osteogenic and chondrogenic differentiation.","date":"2013","source":"PloS 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Bank.","date":"2023","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/37750380","citation_count":5,"is_preprint":false},{"pmid":"32850455","id":"PMC_32850455","title":"BRE Promotes Esophageal Squamous Cell Carcinoma Growth by Activating AKT Signaling.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32850455","citation_count":5,"is_preprint":false},{"pmid":"28871137","id":"PMC_28871137","title":"C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation.","date":"2017","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/28871137","citation_count":5,"is_preprint":false},{"pmid":"15930177","id":"PMC_15930177","title":"Blocking BRE expression in Leydig cells inhibits steroidogenesis by down-regulating 3beta-hydroxysteroid dehydrogenase.","date":"2005","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15930177","citation_count":5,"is_preprint":false},{"pmid":"39468152","id":"PMC_39468152","title":"LncRNA BRE-AS1 regulates the JAK2/STAT3-mediated inflammatory activation via the miR-30b-5p/SOC3 axis in THP-1 cells.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39468152","citation_count":5,"is_preprint":false},{"pmid":"32495865","id":"PMC_32495865","title":"LncRNA BRE-AS1 acts as a tumor suppressor factor in bladder cancer via mediating STAT3.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32495865","citation_count":5,"is_preprint":false},{"pmid":"39462835","id":"PMC_39462835","title":"Preoperative chemo-CIRT in Re/BRe pancreatic cancer: Insights from a multicenter prospective phase II clinical study (NCT03822936).","date":"2024","source":"Tumori","url":"https://pubmed.ncbi.nlm.nih.gov/39462835","citation_count":4,"is_preprint":false},{"pmid":"9071336","id":"PMC_9071336","title":"Paclitaxel, 5-fluorouracil, and folinic acid in metastatic breast cancer: BRE-26, a phase II trial.","date":"1997","source":"Seminars in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/9071336","citation_count":4,"is_preprint":false},{"pmid":"33050379","id":"PMC_33050379","title":"Babam2 Regulates Cell Cycle Progression and Pluripotency in Mouse Embryonic Stem Cells as Revealed by Induced DNA Damage.","date":"2020","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/33050379","citation_count":4,"is_preprint":false},{"pmid":"15127289","id":"PMC_15127289","title":"Tissue specific expression and sequence analysis of a stress responsive gene Bre in adult golden hamster (Mesocricetus auratus).","date":"2004","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/15127289","citation_count":3,"is_preprint":false},{"pmid":"38733316","id":"PMC_38733316","title":"Clinical value of BRE-AS1 in myocardial infarction and its role in myocardial infarction-induced cardiac muscle cell apoptosis.","date":"2024","source":"Scandinavian cardiovascular journal : SCJ","url":"https://pubmed.ncbi.nlm.nih.gov/38733316","citation_count":2,"is_preprint":false},{"pmid":"31111759","id":"PMC_31111759","title":"C-terminal BRE inhibits cellular proliferation and increases sensitivity to chemotherapeutic drugs of MLL-AF9 acute myeloid leukemia cells.","date":"2019","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/31111759","citation_count":1,"is_preprint":false},{"pmid":"27190043","id":"PMC_27190043","title":"Molecular Cloning, Expression, and Identification of Bre Genes Involved in Glycosphingolipids Synthesis in Helicoverpa armigera (Lepidoptera: Noctuidae).","date":"2016","source":"Journal of economic entomology","url":"https://pubmed.ncbi.nlm.nih.gov/27190043","citation_count":1,"is_preprint":false},{"pmid":"37530129","id":"PMC_37530129","title":"Long non-coding RNA BRE-AS1 inhibits proliferation, migration and invasion of clear cell renal cell carcinoma by downregulating miR-106b-5p.","date":"2023","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/37530129","citation_count":1,"is_preprint":false},{"pmid":"28219220","id":"PMC_28219220","title":"[Clinical significance of expressions of EVI1 and BRE genes in 47 acute leukemia patients with MLL rearrangement].","date":"2017","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/28219220","citation_count":0,"is_preprint":false},{"pmid":"23470150","id":"PMC_23470150","title":"Identification of the first mutation in a BRE motif of the β-globin gene and its inheritance with two other α-globin gene mutations in a Lebanese family.","date":"2013","source":"Hemoglobin","url":"https://pubmed.ncbi.nlm.nih.gov/23470150","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.03.25323252","title":"Uncovering research patterns of a middle-income country: A Comprehensive Study of Peru’s Specialized Health Institutes’ Scientific Output (1991-2021)","date":"2025-03-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.03.25323252","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.21.624663","title":"<i>Aspergillus nidulans</i>Transcription Factor BrlA is Utilized in a Conidiation-Independent Response to Cell-Wall Stress","date":"2024-11-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.21.624663","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":27630,"output_tokens":3841,"usd":0.070252},"stage2":{"model":"claude-opus-4-6","input_tokens":7303,"output_tokens":2472,"usd":0.147473},"total_usd":0.217725,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"BRE was identified as a binding partner of the juxtamembrane domain of the p55 TNF receptor (TNFR1) via yeast two-hybrid screen, confirmed by in vitro biochemical assay with recombinant fusion proteins and co-immunoprecipitation in transfected mammalian cells; overexpression of BRE inhibited TNF-induced NF-κB activation.\",\n      \"method\": \"Yeast two-hybrid, in vitro pulldown with recombinant proteins, co-immunoprecipitation, NF-κB reporter assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional NF-κB assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9737713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BRE binds to the cytoplasmic domain of Fas (in addition to TNFR1) and confers resistance to apoptosis induced by TNF-α, anti-Fas antibody, and stress stimuli by inhibiting the mitochondrial apoptotic pathway without translocating to the mitochondria or nucleus and without reducing truncated Bid levels; BRE dissociates from TNFR1 (but not Fas) upon receptor ligation and shows increased association with phosphorylated, sumoylated, and ubiquitinated proteins after death receptor stimulation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, apoptosis assays, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, KD, OE, fractionation) with specific mechanistic readouts\",\n      \"pmids\": [\"15465831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRE and NBA1/MERIT40 interact via the C-terminal conserved motif of NBA1 and the C-terminal UEV domain of BRE; this interaction is required for the integrity of both BRCC36-containing DUB complexes (nuclear Abraxas complex and cytoplasmic ABRO1 complex), for cellular resistance to ionizing radiation, and for BRCA1 recruitment to DNA damage sites.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, domain mapping, ionizing radiation survival assay, immunofluorescence for BRCA1 foci\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping, functional rescue experiments, replicated in two complexes\",\n      \"pmids\": [\"21282113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Liver-specific transgenic BRE mice are significantly resistant to Fas-mediated lethal hepatic apoptosis in vivo, confirming BRE's anti-apoptotic function in a whole-animal model; post-transcriptional regulation of BRE level occurs in liver but not in cell lines.\",\n      \"method\": \"Transgenic mouse model, Fas-induced hepatic apoptosis challenge, immunohistochemistry\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss/gain-of-function with specific phenotypic readout, confirms prior mechanistic findings\",\n      \"pmids\": [\"17704801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BRE (BRCC45) promotes survival of BRCA2-deficient cells by facilitating deubiquitylation of CDC25A phosphatase through recruitment of the deubiquitylase USP7 to CDC25A in the presence of DNA damage, thereby stabilizing CDC25A and deregulating cell cycle checkpoint control.\",\n      \"method\": \"Insertional mutagenesis screen, co-immunoprecipitation, ubiquitylation assay, cell viability assay, overexpression and knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical co-IP establishing USP7 recruitment, functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"29416040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRE maintains the cellular protein level of XIAP (the most potent endogenous caspase inhibitor) to mediate its anti-apoptotic function; shRNA-mediated depletion of BRE downregulates XIAP protein and mRNA, sensitizes cells to both extrinsic and intrinsic apoptosis, and reconstitution of BRE restores XIAP levels and apoptotic resistance.\",\n      \"method\": \"shRNA knockdown, reconstitution, Western blot, apoptosis assays, qRT-PCR\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD plus reconstitution with specific molecular readout (XIAP), multiple methods\",\n      \"pmids\": [\"24395041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRE is required for BRCA1-A complex recruitment to DNA damage sites and for homologous recombination (HR)-dependent DNA repair; BRE-/- fibroblasts show impaired γ-H2AX foci resolution, earlier replicative senescence, and increased DNA damage-induced premature senescence.\",\n      \"method\": \"BRE knockout mouse fibroblasts, immunofluorescence for γ-H2AX foci and BRCA1 recruitment, SA-β-Gal senescence assay, HR assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with multiple orthogonal readouts (HR assay, foci resolution, senescence)\",\n      \"pmids\": [\"27001068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRE facilitates skeletal muscle regeneration by promoting satellite cell motility and chemotactic migration toward SDF-1α, and protects CXCR4 from SDF-1α-induced degradation; BRE-KO mice show impaired muscle regeneration with fewer Pax7+ satellite cells and reduced myofiber formation.\",\n      \"method\": \"BRE knockout mouse model, tibialis anterior injury model, time-lapse microscopy, chemotaxis assay, immunofluorescence\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model with specific readouts; CXCR4 protection is single-lab finding\",\n      \"pmids\": [\"26740569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRE promotes osteoblastic differentiation by physically interacting with p53 and promoting Mdm2-mediated p53 ubiquitination and degradation; BRE knockdown leads to increased p53, p21, and Mdm2, and inhibition of p53 rescues the impaired osteogenesis caused by BRE loss.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, p53 inhibitor rescue, ubiquitination assay, alkaline phosphatase activity, mineralization assay\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional rescue with p53 inhibitor; single lab\",\n      \"pmids\": [\"28436570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Babam2 (BRE) negatively regulates osteoclastogenesis by interacting with Hey1 to inhibit Nfatc1 transcription; Babam2 knockdown accelerates osteoclast formation, overexpression blocks it, and Hey1 silencing abolishes Babam2's inhibitory effects; Babam2-transgenic mice show increased bone mass and resistance to LPS-induced bone resorption.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, transgenic mouse model, LPS-induced calvarial bone resorption model, Nfatc1 reporter assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis (Hey1 KD rescues), Co-IP, in vivo transgenic model; single lab\",\n      \"pmids\": [\"35864959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Blocking BRE expression in Leydig cells (mLTC-1) impairs steroidogenesis specifically at the pregnenolone-to-progesterone conversion step by downregulating 3β-hydroxysteroid dehydrogenase type I (3β-HSDI) mRNA, without affecting cAMP production, StAR, or P450scc expression.\",\n      \"method\": \"Antisense transfection, steroid hormone measurement by RIA, RT-PCR, cAMP assay\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — antisense knockdown with specific enzymatic readout; single lab, single method approach\",\n      \"pmids\": [\"15930177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of Babam2 in mouse embryonic stem cells leads to abnormal G1 phase retention after DNA damage (gamma irradiation or doxorubicin), with degradation of key cell cycle regulators CDC25A and CDK2, prolonged p53 expression, and p53-mediated inhibition of Nanog and G1/S progression, reducing developmental pluripotency.\",\n      \"method\": \"Babam2 knockout mESCs, flow cytometry cell cycle analysis, Western blot for CDC25A/CDK2/p53/Nanog, gamma irradiation and doxorubicin treatment\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model with multiple molecular and cellular readouts; single lab\",\n      \"pmids\": [\"33050379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRE expression in the chick neural tube regulates neural crest cell (NCC) migration, neurite outgrowth, and indirectly somite development; overexpression of BRE increases HNK-1+ NCC migration and TuJ-1+ neurite outgrowth and affects BMP4 and Shh expression in the neural tube.\",\n      \"method\": \"In ovo electroporation (overexpression/knockdown), in situ hybridization, immunofluorescence, time-lapse imaging in chick embryo\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss-of-function in vivo with specific cellular readouts; ortholog in avian model\",\n      \"pmids\": [\"25568339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRE overexpression activates AKT phosphorylation in esophageal squamous cell carcinoma cells to promote cell cycle progression and apoptotic resistance; AKT pathway inhibition by MK2206 reverses BRE-induced growth and survival effects.\",\n      \"method\": \"Overexpression, siRNA knockdown, AKT inhibitor (MK2206) treatment, Western blot, cell cycle analysis, xenograft model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with AKT inhibitor plus in vivo validation; single lab\",\n      \"pmids\": [\"32850455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BRE knockdown in C2C12 cells reduces prohibitin and p53 expression and increases cell proliferation, while BRE overexpression upregulates p53 and prohibitin and decreases proliferation; differentially expressed proteins upon BRE manipulation include targets/crosstalk partners of NF-κB.\",\n      \"method\": \"siRNA knockdown, overexpression, comparative 2D proteomics, MALDI-TOF MS, cell proliferation assay\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — proteomics with functional follow-up; single lab\",\n      \"pmids\": [\"16518872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human BRE is expressed as multiple mRNA isoforms (at least six) generated by alternative splicing at either end of the gene; isoform alpha(a), encoding canonical BRE with a C-terminal peroxisomal targeting sequence, is the most abundant; BRE isoforms are downregulated in monocytes by LPS stimulation.\",\n      \"method\": \"RT-PCR, Northern blot, sequence analysis of cDNA isoforms\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — molecular characterization of splice variants with functional inference; single lab\",\n      \"pmids\": [\"11676476\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BABAM2 (BRE/BRCC45) is a multifunctional adaptor protein that: (1) interacts with TNFR1 and Fas cytoplasmic domains to inhibit death receptor-mediated NF-κB activation and mitochondrial apoptosis; (2) serves as a core structural component of two distinct BRCC36 deubiquitinase complexes (nuclear BRCA1-A and cytoplasmic BRISC) through its UEV domain interaction with NBA1/MERIT40; (3) facilitates homologous recombination-based DNA repair by supporting BRCA1-A complex recruitment to damage sites; (4) stabilizes CDC25A by recruiting USP7 for its deubiquitylation in response to DNA damage; (5) maintains XIAP protein levels to broadly suppress caspase activation; and (6) promotes p53 degradation via Mdm2-mediated ubiquitination and negatively regulates osteoclastogenesis by interacting with Hey1 to suppress Nfatc1 transcription.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BABAM2 (BRE/BRCC45) is a multifunctional adaptor protein that integrates death receptor signaling, DNA damage repair, and cell cycle checkpoint control. It binds the cytoplasmic domains of TNFR1 and Fas to suppress NF-κB activation and mitochondrial apoptosis, in part by maintaining XIAP protein levels [PMID:9737713, PMID:15465831, PMID:24395041, PMID:17704801]. Through its C-terminal UEV domain, BABAM2 interacts with NBA1/MERIT40 and is essential for the structural integrity of two BRCC36 deubiquitinase complexes—the nuclear BRCA1-A complex and the cytoplasmic BRISC complex—thereby supporting homologous recombination-based DNA repair and ionizing radiation resistance [PMID:21282113, PMID:27001068]. BABAM2 also recruits USP7 to deubiquitylate and stabilize CDC25A phosphatase after DNA damage, promotes Mdm2-mediated p53 degradation to facilitate osteoblast differentiation, and negatively regulates osteoclastogenesis by cooperating with Hey1 to repress Nfatc1 transcription [PMID:29416040, PMID:28436570, PMID:35864959].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying BABAM2 as a TNFR1-interacting protein established its initial link to death receptor signaling and NF-κB suppression.\",\n      \"evidence\": \"Yeast two-hybrid screen with TNFR1 juxtamembrane domain, confirmed by reciprocal Co-IP and NF-κB reporter assay in mammalian cells\",\n      \"pmids\": [\"9737713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which BRE inhibits NF-κB was not defined\", \"No endogenous validation at physiological expression levels\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that BABAM2 also binds Fas and protects against both extrinsic and stress-induced apoptosis via the mitochondrial pathway broadened its role from a single-receptor partner to a general anti-apoptotic adaptor.\",\n      \"evidence\": \"Co-IP with Fas, siRNA knockdown, subcellular fractionation, and apoptosis assays showing mitochondrial pathway inhibition without BRE translocation\",\n      \"pmids\": [\"15465831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mitochondrial target of BRE-mediated protection not identified\", \"Post-translational modification changes on BRE after receptor stimulation not functionally assigned\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo validation using liver-specific BRE transgenic mice confirmed the anti-apoptotic function is physiologically relevant in Fas-mediated hepatic injury.\",\n      \"evidence\": \"Transgenic mouse model challenged with Fas agonist, with histological and survival readouts\",\n      \"pmids\": [\"17704801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRE anti-apoptotic function in vivo operates through XIAP or another mechanism was untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping the BRE–NBA1/MERIT40 interaction through the UEV domain established BABAM2 as a core structural subunit required for the integrity of both the nuclear BRCA1-A and cytoplasmic BRISC deubiquitinase complexes.\",\n      \"evidence\": \"Reciprocal Co-IP with domain truncation mapping, siRNA knockdown disrupting both complexes, IR survival and BRCA1 foci assays\",\n      \"pmids\": [\"21282113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of UEV–NBA1 interaction not resolved at atomic level\", \"Relative contribution of BRCA1-A versus BRISC to radiation resistance not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that BRE maintains XIAP protein and mRNA levels identified a specific molecular effector through which BABAM2 confers broad caspase-dependent apoptotic resistance.\",\n      \"evidence\": \"shRNA knockdown and reconstitution restoring XIAP levels and apoptotic resistance in cultured cells\",\n      \"pmids\": [\"24395041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which BRE regulates XIAP mRNA is unknown\", \"Whether XIAP regulation is linked to BRE's death receptor binding is untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"BRE knockout fibroblasts established that BABAM2 is required for BRCA1-A complex recruitment to DNA damage sites, homologous recombination efficiency, and prevention of premature senescence.\",\n      \"evidence\": \"BRE−/− mouse fibroblasts with HR reporter assay, γ-H2AX foci resolution kinetics, and senescence-associated β-galactosidase staining\",\n      \"pmids\": [\"27001068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether senescence phenotype is entirely HR-dependent or involves additional BRE functions not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that BRE promotes Mdm2-mediated p53 ubiquitination and degradation revealed a mechanism connecting BABAM2 to osteoblast differentiation and cell fate control beyond DNA repair.\",\n      \"evidence\": \"Co-IP of BRE with p53, ubiquitination assay, siRNA knockdown impairing osteogenesis rescued by p53 inhibitor\",\n      \"pmids\": [\"28436570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BRE–p53 interaction is direct or bridged through Mdm2 not definitively resolved\", \"Single-lab finding awaiting independent replication\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of BABAM2 as a recruiter of USP7 deubiquitinase to stabilize CDC25A linked its adaptor function to cell cycle checkpoint deregulation and survival of BRCA2-deficient cells.\",\n      \"evidence\": \"Insertional mutagenesis screen in BRCA2-deficient cells, Co-IP of BRE–USP7–CDC25A, ubiquitylation assays, knockdown and overexpression\",\n      \"pmids\": [\"29416040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRE-mediated CDC25A stabilization occurs in wild-type DNA damage contexts or is specific to BRCA2 loss not fully tested\", \"Structural basis of USP7 recruitment by BRE unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that BABAM2 partners with Hey1 to repress Nfatc1 transcription and suppress osteoclastogenesis extended its adaptor role to transcriptional regulation of bone homeostasis.\",\n      \"evidence\": \"Co-IP of BRE with Hey1, Hey1 knockdown abolishing BRE's inhibitory effect on osteoclasts, transgenic mice with increased bone mass and resistance to LPS-induced bone resorption\",\n      \"pmids\": [\"35864959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BRE–Hey1 interaction is direct or part of a larger complex is unresolved\", \"Single-lab finding in mouse model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BABAM2 coordinates its diverse functions—death receptor signaling, BRCA1-A/BRISC complex integrity, USP7-CDC25A stabilization, XIAP maintenance, and transcriptional co-repression—through a single adaptor remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length BABAM2 exists\", \"Whether distinct pools of BABAM2 serve different complexes or context-dependent switching occurs is unknown\", \"Relative contribution of each function to organismal phenotypes is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 13]}\n    ],\n    \"complexes\": [\n      \"BRCA1-A complex\",\n      \"BRISC complex\"\n    ],\n    \"partners\": [\n      \"BABAM1\",\n      \"BRCC3\",\n      \"USP7\",\n      \"TNFRSF1A\",\n      \"FAS\",\n      \"XIAP\",\n      \"TP53\",\n      \"HEY1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}