{"gene":"BABAM2","run_date":"2026-06-09T22:02:44","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 using recombinant fusion proteins and co-immunoprecipitation in transfected mammalian cells. Overexpression of BRE inhibited TNF-induced NF-κB activation, indicating BRE modulates TNF-α signal transduction.","method":"Yeast two-hybrid screen, in vitro binding assay with recombinant proteins, co-immunoprecipitation, NF-κB reporter assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus in vitro binding plus functional reporter assay, foundational study replicated by later work","pmids":["9737713"],"is_preprint":false},{"year":2004,"finding":"BRE binds to Fas (in addition to TNFR1) and inhibits the mitochondrial apoptotic pathway downstream of death receptor activation. BRE dissociates rapidly from TNFR1 (but not Fas) upon receptor ligation, and associates with phosphorylated, sumoylated, and ubiquitinated proteins after death receptor stimulation. Knockdown of BRE by siRNA increased apoptosis specifically to death receptor-mediated (TNF-α) stimuli, but not etoposide, establishing a specific physiological role in death receptor-mediated apoptosis.","method":"Co-immunoprecipitation, overexpression, siRNA knockdown, flow cytometry apoptosis assays, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, siRNA, gain-of-function) in single rigorous study, mechanistically specific finding replicated by subsequent studies","pmids":["15465831"],"is_preprint":false},{"year":2011,"finding":"BRE is a common component of two distinct BRCC36-containing deubiquitinase complexes: the nuclear Abraxas-BRCA1 complex and the cytoplasmic ABRO1 complex. BRE interacts with NBA1/MERIT40 through a C-terminal UEV domain of BRE and a C-terminal conserved motif of NBA1; this NBA1-BRE interaction is critical for maintaining the integrity of both complexes. Knockdown of BRE leads to decreased levels of components of both BRCC36-containing complexes, and the NBA1-BRE interaction is required for cellular resistance to ionizing radiation and for BRCA1 recruitment to DNA damage sites.","method":"Co-immunoprecipitation, siRNA knockdown, domain-mapping deletion mutants, clonogenic survival assay, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, functional rescue, and multiple orthogonal methods in a single study","pmids":["21282113"],"is_preprint":false},{"year":2018,"finding":"BRE (BRCC45) promotes survival of BRCA2-deficient cells by stabilizing CDC25A phosphatase through recruitment of deubiquitylase USP7. In the presence of DNA damage, BRE facilitates USP7-mediated deubiquitylation of CDC25A, preventing its degradation and enabling cell cycle progression.","method":"Insertional mutagenesis screen, co-immunoprecipitation, ubiquitylation assay, immunoblot, cell viability assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection using multiple orthogonal methods (screen, Co-IP, ubiquitylation assay) with functional validation","pmids":["29416040"],"is_preprint":false},{"year":2014,"finding":"BRE maintains cellular XIAP protein levels (the most potent endogenous caspase inhibitor) through a mechanism that involves transcriptional and post-transcriptional regulation of XIAP. shRNA-mediated depletion of BRE reduced XIAP protein and mRNA levels and sensitized cells to apoptosis from both death receptor (TNF-α) and genotoxic (etoposide) stimuli; reconstitution of BRE restored XIAP levels and apoptotic resistance.","method":"shRNA knockdown, reconstitution, immunoblot, RT-PCR, flow cytometry apoptosis assay, protein turnover assay","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO/reconstitution with defined phenotype (XIAP regulation), multiple methods, single lab","pmids":["24395041"],"is_preprint":false},{"year":2005,"finding":"Blocking BRE expression in mouse Leydig tumor cells (using antisense probes) impaired steroidogenesis specifically at the pregnenolone-to-progesterone conversion step, accompanied by reduced 3β-hydroxysteroid dehydrogenase type I (3β-HSDI) mRNA expression, without affecting StAR or P450scc expression or cAMP production. This establishes a role for BRE in steroidogenesis through regulation of 3β-HSD transcription.","method":"Antisense transfection, steroid hormone measurement (RIA), RT-PCR, cAMP assay","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific biochemical readouts, single lab, two orthogonal assay types","pmids":["15930177"],"is_preprint":false},{"year":2016,"finding":"BRE is required for the BRCA1-A complex recruitment and homologous recombination (HR)-dependent DNA repair. BRE-/- fibroblasts showed persistent γ-H2AX foci after gamma irradiation, impaired BRCA1-A complex recruitment to DNA damage sites, and earlier replicative senescence compared to wild-type cells.","method":"Knockout mouse fibroblasts, immunofluorescence (γ-H2AX foci), SA-β-Gal senescence assay, gamma irradiation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with multiple phenotypic readouts, single lab","pmids":["27001068"],"is_preprint":false},{"year":2017,"finding":"BRE promotes Mdm2-mediated p53 ubiquitination and degradation by physically interacting with p53, thereby promoting osteoblast differentiation. Knockdown of BRE in bone marrow mesenchymal cells led to p53 pathway activation (increased p53, p21, Mdm2); inhibition of p53 by siRNA or pifithrin-α rescued the impaired osteogenesis caused by BRE knockdown.","method":"siRNA knockdown, overexpression, co-immunoprecipitation (BRE-p53 interaction), p53 ubiquitination assay, alkaline phosphatase activity, mineralization assay, in vivo osteogenesis model","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction, ubiquitination assay, genetic epistasis via p53 rescue, 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 accelerated osteoclast formation; Babam2 overexpression blocked it. Transgenic Babam2 mice had increased bone mass and reduced bone resorption. Silencing Hey1 diminished the inhibitory effects of Babam2 on osteoclastogenesis, placing Hey1 downstream of Babam2 in this pathway.","method":"Co-immunoprecipitation (Babam2-Hey1 interaction), transgenic mice, knockdown/overexpression, Nfatc1 reporter assay, osteoclast differentiation assay, LPS-induced bone resorption model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction, genetic epistasis (Hey1 rescue), in vivo transgenic model, single lab","pmids":["35864959"],"is_preprint":false},{"year":2020,"finding":"Loss of Babam2 (BRE) in mouse embryonic stem cells causes abnormal G1 phase retention in response to DNA damage (gamma irradiation or doxorubicin), with degradation of CDC25A and CDK2, prolonged p53 activation, and p53-mediated suppression of Nanog expression, reducing developmental pluripotency.","method":"Babam2 knockout mESCs, flow cytometry (cell cycle), immunoblot (CDC25A, CDK2, p53, Nanog), gamma irradiation, doxorubicin treatment","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with multiple molecular readouts, single lab, consistent with published BRE/CDC25A mechanism","pmids":["33050379"],"is_preprint":false},{"year":2016,"finding":"BRE facilitates skeletal muscle satellite cell migration and differentiation during muscle regeneration. BRE-KO mice showed impaired muscle regeneration with fewer Pax7+ satellite cells. BRE normally protects CXCR4 from SDF-1α-induced degradation, thereby maintaining responsiveness to the chemoattractant SDF-1α. BRE-KO satellite cells showed significantly reduced velocity of movement and diminished chemotactic response to SDF-1α.","method":"Knockout mouse model, tibialis anterior injury model, time-lapse microscopy, chemotaxis assay, immunofluorescence, immunoblot (CXCR4 degradation)","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with defined cellular phenotype and molecular mechanism (CXCR4 stabilization), single lab","pmids":["26740569"],"is_preprint":false},{"year":2017,"finding":"BRE overexpression in the chick neural tube increased HNK-1+ neural crest cell migration and TuJ-1+ neurite outgrowth, and was associated with changes in BMP4 and Shh expression in the neural tube. Silencing BRE produced inverse effects. BRE effects on somitogenesis were indirect, mediated through altered BMP4/Shh signaling.","method":"In ovo electroporation (overexpression and knockdown), in situ hybridization, immunofluorescence, cell cycle analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional perturbation (OE and KD) with defined phenotypic readouts in embryo model, single lab","pmids":["25568339"],"is_preprint":false},{"year":2006,"finding":"BRE knockdown by siRNA in C2C12 cells resulted in increased cell proliferation and reduced p53 and prohibitin expression; overexpression of BRE in D122 cells decreased proliferation and upregulated p53 and prohibitin. Proteomic analysis showed BRE regulates prohibitin, 26S proteasome regulatory subunit S14, Akt-3, and carbonic anhydrase III.","method":"siRNA knockdown, overexpression, 2D-gel comparative proteomics, cell proliferation assay, immunoblot","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — bidirectional perturbation, proteomic plus functional assays, single lab","pmids":["16518872"],"is_preprint":false},{"year":2007,"finding":"Liver-specific BRE transgenic mice were significantly resistant to Fas-mediated lethal hepatic apoptosis in vivo, confirming BRE's antiapoptotic role in vivo. The study also revealed post-transcriptional regulation of BRE in normal liver (absent in HCC cells).","method":"Liver-specific BRE transgenic mice, Fas-induced acute hepatitis model, survival analysis, immunohistochemistry","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with defined functional readout (Fas-mediated hepatic apoptosis), single lab, builds on prior mechanistic framework","pmids":["17704801"],"is_preprint":false},{"year":2020,"finding":"BRE overexpression activates AKT phosphorylation and promotes esophageal squamous cell carcinoma (ESCC) cell growth and apoptotic resistance. Pharmacological inhibition of AKT (MK2206) abrogated BRE-induced cell growth, placing AKT signaling downstream of BRE in ESCC cells.","method":"Overexpression, siRNA knockdown, AKT inhibitor (MK2206), immunoblot (p-AKT), cell viability, apoptosis assay, xenograft model","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, AKT activation measured by phospho-blot only, no direct binding shown; pathway placement by inhibitor experiment","pmids":["32850455"],"is_preprint":false},{"year":2001,"finding":"Human BRE is expressed as at least six alternative mRNA isoforms generated by alternative splicing predominantly at either end of the gene. Isoform alpha(a), carrying a C-terminal peroxisomal targeting sequence, is the most abundant. LPS treatment of peripheral blood monocytes downregulates all BRE isoforms.","method":"RT-PCR, Northern blotting, cDNA cloning, sequence analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — characterization of transcript isoforms, single lab, no direct functional comparison of isoforms","pmids":["11676476"],"is_preprint":false}],"current_model":"BABAM2 (BRE/BRCC45) is a multifunctional scaffold/adaptor protein that operates in two distinct BRCC36 deubiquitinase complexes (nuclear BRCA1-A and cytoplasmic BRISC), where its interaction with NBA1/MERIT40 via its C-terminal UEV domain is essential for complex integrity and for recruiting BRCA1 to DNA damage sites for homologous recombination repair; in the cytoplasm it associates with TNFR1 and Fas to inhibit death receptor-triggered mitochondrial apoptosis, maintains XIAP expression, stabilizes CDC25A by recruiting USP7 to counteract DNA damage-induced cell cycle arrest, interacts with p53 to promote Mdm2-mediated p53 ubiquitination and degradation, and interacts with Hey1 to suppress Nfatc1 transcription during osteoclastogenesis."},"narrative":{"mechanistic_narrative":"BABAM2 (BRE/BRCC45) is a scaffold/adaptor protein that integrates two broad cellular programs: DNA-damage response and the control of receptor-triggered apoptosis [PMID:9737713, PMID:21282113]. In the nucleus it is a shared component of two BRCC36-containing deubiquitinase complexes—the BRCA1-A and BRISC/ABRO1 complexes—where its C-terminal UEV domain binds NBA1/MERIT40, an interaction required for complex integrity, cellular resistance to ionizing radiation, and recruitment of BRCA1 to DNA damage sites for homologous-recombination repair [PMID:21282113, PMID:27001068]. Through this DNA-damage axis BABAM2 also stabilizes the CDC25A phosphatase by recruiting the deubiquitylase USP7, opposing CDC25A degradation and permitting cell-cycle progression after damage; loss of BABAM2 causes G1 retention, CDC25A/CDK2 loss, and prolonged p53 activation [PMID:29416040, PMID:33050379]. At the cell surface, BABAM2 was first identified as a binding partner of the TNFR1 juxtamembrane domain that dampens TNF-induced NF-κB signaling, and it additionally binds Fas to inhibit the mitochondrial apoptotic pathway downstream of death receptors, an antiapoptotic role confirmed in vivo by resistance of liver-specific transgenic mice to Fas-mediated hepatic apoptosis [PMID:9737713, PMID:15465831, PMID:17704801]. BABAM2 further restrains apoptosis by maintaining XIAP protein and mRNA levels [PMID:24395041]. The protein also participates in developmental and lineage programs: it promotes Mdm2-mediated p53 ubiquitination and degradation to favor osteoblast differentiation, suppresses osteoclastogenesis by interacting with Hey1 to inhibit Nfatc1 transcription, and supports satellite-cell migration during muscle regeneration by protecting CXCR4 from SDF-1α-induced degradation [PMID:28436570, PMID:35864959, PMID:26740569].","teleology":[{"year":1998,"claim":"Established the first molecular role of BABAM2 by identifying it as a TNFR1-associated factor that modulates death-receptor signaling, framing the protein as a regulator of cytokine signal transduction.","evidence":"Yeast two-hybrid, in vitro binding, Co-IP, and NF-κB reporter assay in mammalian cells","pmids":["9737713"],"confidence":"High","gaps":["Did not define how BABAM2 binding alters downstream NF-κB components","No structural basis for the TNFR1 interaction"]},{"year":2004,"claim":"Extended the receptor repertoire to Fas and localized BABAM2's antiapoptotic action to the mitochondrial pathway downstream of death receptors, establishing a stimulus-specific physiological role.","evidence":"Co-IP, siRNA knockdown, flow-cytometry apoptosis assays, and subcellular fractionation","pmids":["15465831"],"confidence":"High","gaps":["Identity of the phospho/sumoylated/ubiquitinated partners engaged after receptor ligation not resolved","Mechanism of differential dissociation from TNFR1 versus Fas unknown"]},{"year":2011,"claim":"Defined BABAM2 as a structural hub of both BRCC36 deubiquitinase complexes, showing its UEV-domain interaction with NBA1/MERIT40 is required for complex integrity and BRCA1 recruitment, unifying its DNA-damage role.","evidence":"Reciprocal Co-IP with deletion-based domain mapping, siRNA knockdown, clonogenic survival, and immunofluorescence","pmids":["21282113"],"confidence":"High","gaps":["Catalytic contribution of BABAM2 to deubiquitination, if any, not established","How nuclear versus cytoplasmic complex assembly is partitioned unaddressed"]},{"year":2016,"claim":"Confirmed in a clean knockout system that BABAM2 is required for BRCA1-A recruitment and HR repair, linking its loss to persistent damage signaling and premature senescence.","evidence":"BRE-/- fibroblasts with γ-H2AX foci imaging, SA-β-Gal assay, and gamma irradiation","pmids":["27001068"],"confidence":"Medium","gaps":["Did not separate scaffold from any signaling function in senescence","Single cell type"]},{"year":2018,"claim":"Identified a USP7/CDC25A axis showing BABAM2 stabilizes CDC25A by recruiting USP7, providing a mechanism by which it sustains cell-cycle progression in BRCA2-deficient cells.","evidence":"Insertional mutagenesis screen, Co-IP, ubiquitylation assay, and viability assays","pmids":["29416040"],"confidence":"High","gaps":["Whether USP7 recruitment is independent of the BRCC36 complexes not clarified","Direct versus bridged BABAM2-USP7 contact undefined"]},{"year":2020,"claim":"Demonstrated in mESCs that BABAM2 loss couples DNA damage to G1 retention, CDC25A/CDK2 degradation, prolonged p53 activity, and Nanog suppression, connecting its cell-cycle role to pluripotency control.","evidence":"Babam2-knockout mESCs with cell-cycle flow cytometry and immunoblotting after irradiation/doxorubicin","pmids":["33050379"],"confidence":"Medium","gaps":["Causal chain from CDC25A loss to Nanog suppression not fully dissected","Stem-cell-specific factors not separated from general mechanism"]},{"year":2014,"claim":"Showed BABAM2 maintains XIAP at both mRNA and protein levels, providing an additional route by which it confers broad apoptotic resistance to death-receptor and genotoxic stimuli.","evidence":"shRNA depletion with reconstitution, immunoblot, RT-PCR, apoptosis assays, and protein turnover assays","pmids":["24395041"],"confidence":"Medium","gaps":["Molecular mechanism of XIAP transcriptional control unidentified","Direct versus indirect regulation not distinguished"]},{"year":2007,"claim":"Validated the antiapoptotic function in vivo, showing liver-specific BABAM2 transgenic mice resist Fas-mediated lethal hepatic apoptosis.","evidence":"Liver-specific transgenic mice in a Fas-induced hepatitis model with survival analysis and IHC","pmids":["17704801"],"confidence":"Medium","gaps":["Did not map the in vivo molecular effectors","Post-transcriptional regulation of BABAM2 in liver mechanistically unexplained"]},{"year":2017,"claim":"Connected BABAM2 to the p53/Mdm2 axis in skeletal lineage cells, showing it promotes Mdm2-mediated p53 degradation to enable osteoblast differentiation.","evidence":"siRNA/overexpression, Co-IP for BABAM2-p53 interaction, p53 ubiquitination assay, and osteogenesis assays in vitro and in vivo","pmids":["28436570"],"confidence":"Medium","gaps":["Whether BABAM2 directly stimulates Mdm2 activity or merely scaffolds unknown","Relationship to its DNA-damage p53 effects not reconciled"]},{"year":2022,"claim":"Established BABAM2 as a negative regulator of osteoclastogenesis acting through a Hey1-Nfatc1 transcriptional axis, supported by transgenic mice with increased bone mass.","evidence":"Co-IP for BABAM2-Hey1 interaction, transgenic mice, knockdown/overexpression, Nfatc1 reporter, and bone resorption models","pmids":["35864959"],"confidence":"Medium","gaps":["How Hey1 binding represses Nfatc1 transcription mechanistically unresolved","Relationship to the BRCC36 complexes unaddressed"]},{"year":2016,"claim":"Identified a role in muscle regeneration whereby BABAM2 supports satellite-cell migration by protecting CXCR4 from SDF-1α-induced degradation.","evidence":"Knockout mice with muscle injury model, time-lapse and chemotaxis assays, and CXCR4 immunoblotting","pmids":["26740569"],"confidence":"Medium","gaps":["Molecular mechanism of CXCR4 stabilization not defined","Link to deubiquitinase complex activity untested"]},{"year":null,"claim":"How BABAM2's well-defined scaffolding role in nuclear/cytoplasmic deubiquitinase complexes mechanistically connects to its diverse tissue-specific functions (death-receptor signaling, p53/Mdm2, Hey1-Nfatc1, CXCR4 stabilization) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking the UEV domain to the multiple receptor and transcription-factor partners","Whether the same molecular activity underlies all reported roles is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"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":[1,4,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,9]}],"complexes":["BRCA1-A complex","BRISC complex"],"partners":["NBA1/MERIT40","TNFR1","FAS","USP7","TP53","HEY1","CXCR4"],"other_free_text":[]}},"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":26,"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":"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":23,"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":"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":"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":"11676476","id":"PMC_11676476","title":"Expression of human BRE in multiple isoforms.","date":"2001","source":"Biochemical and biophysical research 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/14565866","citation_count":7,"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":6,"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":"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 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endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15930177","citation_count":5,"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":"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":"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 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Overexpression of BRE inhibited TNF-induced NF-κB activation, indicating BRE modulates TNF-α signal transduction.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay with recombinant proteins, co-immunoprecipitation, NF-κB reporter assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus in vitro binding plus functional reporter assay, foundational study replicated by later work\",\n      \"pmids\": [\"9737713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BRE binds to Fas (in addition to TNFR1) and inhibits the mitochondrial apoptotic pathway downstream of death receptor activation. BRE dissociates rapidly from TNFR1 (but not Fas) upon receptor ligation, and associates with phosphorylated, sumoylated, and ubiquitinated proteins after death receptor stimulation. Knockdown of BRE by siRNA increased apoptosis specifically to death receptor-mediated (TNF-α) stimuli, but not etoposide, establishing a specific physiological role in death receptor-mediated apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, siRNA knockdown, flow cytometry apoptosis assays, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, siRNA, gain-of-function) in single rigorous study, mechanistically specific finding replicated by subsequent studies\",\n      \"pmids\": [\"15465831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRE is a common component of two distinct BRCC36-containing deubiquitinase complexes: the nuclear Abraxas-BRCA1 complex and the cytoplasmic ABRO1 complex. BRE interacts with NBA1/MERIT40 through a C-terminal UEV domain of BRE and a C-terminal conserved motif of NBA1; this NBA1-BRE interaction is critical for maintaining the integrity of both complexes. Knockdown of BRE leads to decreased levels of components of both BRCC36-containing complexes, and the NBA1-BRE interaction is required for cellular resistance to ionizing radiation and for BRCA1 recruitment to DNA damage sites.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, domain-mapping deletion mutants, clonogenic survival assay, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, functional rescue, and multiple orthogonal methods in a single study\",\n      \"pmids\": [\"21282113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BRE (BRCC45) promotes survival of BRCA2-deficient cells by stabilizing CDC25A phosphatase through recruitment of deubiquitylase USP7. In the presence of DNA damage, BRE facilitates USP7-mediated deubiquitylation of CDC25A, preventing its degradation and enabling cell cycle progression.\",\n      \"method\": \"Insertional mutagenesis screen, co-immunoprecipitation, ubiquitylation assay, immunoblot, cell viability assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection using multiple orthogonal methods (screen, Co-IP, ubiquitylation assay) with functional validation\",\n      \"pmids\": [\"29416040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRE maintains cellular XIAP protein levels (the most potent endogenous caspase inhibitor) through a mechanism that involves transcriptional and post-transcriptional regulation of XIAP. shRNA-mediated depletion of BRE reduced XIAP protein and mRNA levels and sensitized cells to apoptosis from both death receptor (TNF-α) and genotoxic (etoposide) stimuli; reconstitution of BRE restored XIAP levels and apoptotic resistance.\",\n      \"method\": \"shRNA knockdown, reconstitution, immunoblot, RT-PCR, flow cytometry apoptosis assay, protein turnover assay\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/reconstitution with defined phenotype (XIAP regulation), multiple methods, single lab\",\n      \"pmids\": [\"24395041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Blocking BRE expression in mouse Leydig tumor cells (using antisense probes) impaired steroidogenesis specifically at the pregnenolone-to-progesterone conversion step, accompanied by reduced 3β-hydroxysteroid dehydrogenase type I (3β-HSDI) mRNA expression, without affecting StAR or P450scc expression or cAMP production. This establishes a role for BRE in steroidogenesis through regulation of 3β-HSD transcription.\",\n      \"method\": \"Antisense transfection, steroid hormone measurement (RIA), RT-PCR, cAMP assay\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific biochemical readouts, single lab, two orthogonal assay types\",\n      \"pmids\": [\"15930177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRE is required for the BRCA1-A complex recruitment and homologous recombination (HR)-dependent DNA repair. BRE-/- fibroblasts showed persistent γ-H2AX foci after gamma irradiation, impaired BRCA1-A complex recruitment to DNA damage sites, and earlier replicative senescence compared to wild-type cells.\",\n      \"method\": \"Knockout mouse fibroblasts, immunofluorescence (γ-H2AX foci), SA-β-Gal senescence assay, gamma irradiation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"27001068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRE promotes Mdm2-mediated p53 ubiquitination and degradation by physically interacting with p53, thereby promoting osteoblast differentiation. Knockdown of BRE in bone marrow mesenchymal cells led to p53 pathway activation (increased p53, p21, Mdm2); inhibition of p53 by siRNA or pifithrin-α rescued the impaired osteogenesis caused by BRE knockdown.\",\n      \"method\": \"siRNA knockdown, overexpression, co-immunoprecipitation (BRE-p53 interaction), p53 ubiquitination assay, alkaline phosphatase activity, mineralization assay, in vivo osteogenesis model\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction, ubiquitination assay, genetic epistasis via p53 rescue, 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 accelerated osteoclast formation; Babam2 overexpression blocked it. Transgenic Babam2 mice had increased bone mass and reduced bone resorption. Silencing Hey1 diminished the inhibitory effects of Babam2 on osteoclastogenesis, placing Hey1 downstream of Babam2 in this pathway.\",\n      \"method\": \"Co-immunoprecipitation (Babam2-Hey1 interaction), transgenic mice, knockdown/overexpression, Nfatc1 reporter assay, osteoclast differentiation assay, LPS-induced bone resorption model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction, genetic epistasis (Hey1 rescue), in vivo transgenic model, single lab\",\n      \"pmids\": [\"35864959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of Babam2 (BRE) in mouse embryonic stem cells causes abnormal G1 phase retention in response to DNA damage (gamma irradiation or doxorubicin), with degradation of CDC25A and CDK2, prolonged p53 activation, and p53-mediated suppression of Nanog expression, reducing developmental pluripotency.\",\n      \"method\": \"Babam2 knockout mESCs, flow cytometry (cell cycle), immunoblot (CDC25A, CDK2, p53, Nanog), gamma irradiation, doxorubicin treatment\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with multiple molecular readouts, single lab, consistent with published BRE/CDC25A mechanism\",\n      \"pmids\": [\"33050379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRE facilitates skeletal muscle satellite cell migration and differentiation during muscle regeneration. BRE-KO mice showed impaired muscle regeneration with fewer Pax7+ satellite cells. BRE normally protects CXCR4 from SDF-1α-induced degradation, thereby maintaining responsiveness to the chemoattractant SDF-1α. BRE-KO satellite cells showed significantly reduced velocity of movement and diminished chemotactic response to SDF-1α.\",\n      \"method\": \"Knockout mouse model, tibialis anterior injury model, time-lapse microscopy, chemotaxis assay, immunofluorescence, immunoblot (CXCR4 degradation)\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with defined cellular phenotype and molecular mechanism (CXCR4 stabilization), single lab\",\n      \"pmids\": [\"26740569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRE overexpression in the chick neural tube increased HNK-1+ neural crest cell migration and TuJ-1+ neurite outgrowth, and was associated with changes in BMP4 and Shh expression in the neural tube. Silencing BRE produced inverse effects. BRE effects on somitogenesis were indirect, mediated through altered BMP4/Shh signaling.\",\n      \"method\": \"In ovo electroporation (overexpression and knockdown), in situ hybridization, immunofluorescence, cell cycle analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional perturbation (OE and KD) with defined phenotypic readouts in embryo model, single lab\",\n      \"pmids\": [\"25568339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BRE knockdown by siRNA in C2C12 cells resulted in increased cell proliferation and reduced p53 and prohibitin expression; overexpression of BRE in D122 cells decreased proliferation and upregulated p53 and prohibitin. Proteomic analysis showed BRE regulates prohibitin, 26S proteasome regulatory subunit S14, Akt-3, and carbonic anhydrase III.\",\n      \"method\": \"siRNA knockdown, overexpression, 2D-gel comparative proteomics, cell proliferation assay, immunoblot\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — bidirectional perturbation, proteomic plus functional assays, single lab\",\n      \"pmids\": [\"16518872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Liver-specific BRE transgenic mice were significantly resistant to Fas-mediated lethal hepatic apoptosis in vivo, confirming BRE's antiapoptotic role in vivo. The study also revealed post-transcriptional regulation of BRE in normal liver (absent in HCC cells).\",\n      \"method\": \"Liver-specific BRE transgenic mice, Fas-induced acute hepatitis model, survival analysis, immunohistochemistry\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with defined functional readout (Fas-mediated hepatic apoptosis), single lab, builds on prior mechanistic framework\",\n      \"pmids\": [\"17704801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRE overexpression activates AKT phosphorylation and promotes esophageal squamous cell carcinoma (ESCC) cell growth and apoptotic resistance. Pharmacological inhibition of AKT (MK2206) abrogated BRE-induced cell growth, placing AKT signaling downstream of BRE in ESCC cells.\",\n      \"method\": \"Overexpression, siRNA knockdown, AKT inhibitor (MK2206), immunoblot (p-AKT), cell viability, apoptosis assay, xenograft model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, AKT activation measured by phospho-blot only, no direct binding shown; pathway placement by inhibitor experiment\",\n      \"pmids\": [\"32850455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human BRE is expressed as at least six alternative mRNA isoforms generated by alternative splicing predominantly at either end of the gene. Isoform alpha(a), carrying a C-terminal peroxisomal targeting sequence, is the most abundant. LPS treatment of peripheral blood monocytes downregulates all BRE isoforms.\",\n      \"method\": \"RT-PCR, Northern blotting, cDNA cloning, sequence analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — characterization of transcript isoforms, single lab, no direct functional comparison of isoforms\",\n      \"pmids\": [\"11676476\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BABAM2 (BRE/BRCC45) is a multifunctional scaffold/adaptor protein that operates in two distinct BRCC36 deubiquitinase complexes (nuclear BRCA1-A and cytoplasmic BRISC), where its interaction with NBA1/MERIT40 via its C-terminal UEV domain is essential for complex integrity and for recruiting BRCA1 to DNA damage sites for homologous recombination repair; in the cytoplasm it associates with TNFR1 and Fas to inhibit death receptor-triggered mitochondrial apoptosis, maintains XIAP expression, stabilizes CDC25A by recruiting USP7 to counteract DNA damage-induced cell cycle arrest, interacts with p53 to promote Mdm2-mediated p53 ubiquitination and degradation, and interacts with Hey1 to suppress Nfatc1 transcription during osteoclastogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BABAM2 (BRE/BRCC45) is a scaffold/adaptor protein that integrates two broad cellular programs: DNA-damage response and the control of receptor-triggered apoptosis [#0, #2]. In the nucleus it is a shared component of two BRCC36-containing deubiquitinase complexes—the BRCA1-A and BRISC/ABRO1 complexes—where its C-terminal UEV domain binds NBA1/MERIT40, an interaction required for complex integrity, cellular resistance to ionizing radiation, and recruitment of BRCA1 to DNA damage sites for homologous-recombination repair [#2, #6]. Through this DNA-damage axis BABAM2 also stabilizes the CDC25A phosphatase by recruiting the deubiquitylase USP7, opposing CDC25A degradation and permitting cell-cycle progression after damage; loss of BABAM2 causes G1 retention, CDC25A/CDK2 loss, and prolonged p53 activation [#3, #9]. At the cell surface, BABAM2 was first identified as a binding partner of the TNFR1 juxtamembrane domain that dampens TNF-induced NF-\\u03baB signaling, and it additionally binds Fas to inhibit the mitochondrial apoptotic pathway downstream of death receptors, an antiapoptotic role confirmed in vivo by resistance of liver-specific transgenic mice to Fas-mediated hepatic apoptosis [#0, #1, #13]. BABAM2 further restrains apoptosis by maintaining XIAP protein and mRNA levels [#4]. The protein also participates in developmental and lineage programs: it promotes Mdm2-mediated p53 ubiquitination and degradation to favor osteoblast differentiation, suppresses osteoclastogenesis by interacting with Hey1 to inhibit Nfatc1 transcription, and supports satellite-cell migration during muscle regeneration by protecting CXCR4 from SDF-1\\u03b1-induced degradation [#7, #8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the first molecular role of BABAM2 by identifying it as a TNFR1-associated factor that modulates death-receptor signaling, framing the protein as a regulator of cytokine signal transduction.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, Co-IP, and NF-\\u03baB reporter assay in mammalian cells\",\n      \"pmids\": [\"9737713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how BABAM2 binding alters downstream NF-\\u03baB components\", \"No structural basis for the TNFR1 interaction\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the receptor repertoire to Fas and localized BABAM2's antiapoptotic action to the mitochondrial pathway downstream of death receptors, establishing a stimulus-specific physiological role.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, flow-cytometry apoptosis assays, and subcellular fractionation\",\n      \"pmids\": [\"15465831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the phospho/sumoylated/ubiquitinated partners engaged after receptor ligation not resolved\", \"Mechanism of differential dissociation from TNFR1 versus Fas unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined BABAM2 as a structural hub of both BRCC36 deubiquitinase complexes, showing its UEV-domain interaction with NBA1/MERIT40 is required for complex integrity and BRCA1 recruitment, unifying its DNA-damage role.\",\n      \"evidence\": \"Reciprocal Co-IP with deletion-based domain mapping, siRNA knockdown, clonogenic survival, and immunofluorescence\",\n      \"pmids\": [\"21282113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic contribution of BABAM2 to deubiquitination, if any, not established\", \"How nuclear versus cytoplasmic complex assembly is partitioned unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed in a clean knockout system that BABAM2 is required for BRCA1-A recruitment and HR repair, linking its loss to persistent damage signaling and premature senescence.\",\n      \"evidence\": \"BRE-/- fibroblasts with \\u03b3-H2AX foci imaging, SA-\\u03b2-Gal assay, and gamma irradiation\",\n      \"pmids\": [\"27001068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate scaffold from any signaling function in senescence\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a USP7/CDC25A axis showing BABAM2 stabilizes CDC25A by recruiting USP7, providing a mechanism by which it sustains cell-cycle progression in BRCA2-deficient cells.\",\n      \"evidence\": \"Insertional mutagenesis screen, Co-IP, ubiquitylation assay, and viability assays\",\n      \"pmids\": [\"29416040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP7 recruitment is independent of the BRCC36 complexes not clarified\", \"Direct versus bridged BABAM2-USP7 contact undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated in mESCs that BABAM2 loss couples DNA damage to G1 retention, CDC25A/CDK2 degradation, prolonged p53 activity, and Nanog suppression, connecting its cell-cycle role to pluripotency control.\",\n      \"evidence\": \"Babam2-knockout mESCs with cell-cycle flow cytometry and immunoblotting after irradiation/doxorubicin\",\n      \"pmids\": [\"33050379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from CDC25A loss to Nanog suppression not fully dissected\", \"Stem-cell-specific factors not separated from general mechanism\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed BABAM2 maintains XIAP at both mRNA and protein levels, providing an additional route by which it confers broad apoptotic resistance to death-receptor and genotoxic stimuli.\",\n      \"evidence\": \"shRNA depletion with reconstitution, immunoblot, RT-PCR, apoptosis assays, and protein turnover assays\",\n      \"pmids\": [\"24395041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of XIAP transcriptional control unidentified\", \"Direct versus indirect regulation not distinguished\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Validated the antiapoptotic function in vivo, showing liver-specific BABAM2 transgenic mice resist Fas-mediated lethal hepatic apoptosis.\",\n      \"evidence\": \"Liver-specific transgenic mice in a Fas-induced hepatitis model with survival analysis and IHC\",\n      \"pmids\": [\"17704801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map the in vivo molecular effectors\", \"Post-transcriptional regulation of BABAM2 in liver mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected BABAM2 to the p53/Mdm2 axis in skeletal lineage cells, showing it promotes Mdm2-mediated p53 degradation to enable osteoblast differentiation.\",\n      \"evidence\": \"siRNA/overexpression, Co-IP for BABAM2-p53 interaction, p53 ubiquitination assay, and osteogenesis assays in vitro and in vivo\",\n      \"pmids\": [\"28436570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BABAM2 directly stimulates Mdm2 activity or merely scaffolds unknown\", \"Relationship to its DNA-damage p53 effects not reconciled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established BABAM2 as a negative regulator of osteoclastogenesis acting through a Hey1-Nfatc1 transcriptional axis, supported by transgenic mice with increased bone mass.\",\n      \"evidence\": \"Co-IP for BABAM2-Hey1 interaction, transgenic mice, knockdown/overexpression, Nfatc1 reporter, and bone resorption models\",\n      \"pmids\": [\"35864959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How Hey1 binding represses Nfatc1 transcription mechanistically unresolved\", \"Relationship to the BRCC36 complexes unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a role in muscle regeneration whereby BABAM2 supports satellite-cell migration by protecting CXCR4 from SDF-1\\u03b1-induced degradation.\",\n      \"evidence\": \"Knockout mice with muscle injury model, time-lapse and chemotaxis assays, and CXCR4 immunoblotting\",\n      \"pmids\": [\"26740569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of CXCR4 stabilization not defined\", \"Link to deubiquitinase complex activity untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BABAM2's well-defined scaffolding role in nuclear/cytoplasmic deubiquitinase complexes mechanistically connects to its diverse tissue-specific functions (death-receptor signaling, p53/Mdm2, Hey1-Nfatc1, CXCR4 stabilization) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking the UEV domain to the multiple receptor and transcription-factor partners\", \"Whether the same molecular activity underlies all reported roles is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 4, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"complexes\": [\"BRCA1-A complex\", \"BRISC complex\"],\n    \"partners\": [\"NBA1/MERIT40\", \"TNFR1\", \"FAS\", \"USP7\", \"TP53\", \"HEY1\", \"CXCR4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}