Affinage

BABAM2

BRISC and BRCA1-A complex member 2 · UniProt Q9NXR7

Length
383 aa
Mass
43.6 kDa
Annotated
2026-04-28
53 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 High

    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

    PMID:9737713

    Open questions at the time
    • Mechanism by which BRE inhibits NF-κB was not defined
    • No endogenous validation at physiological expression levels
  2. 2004 High

    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

    PMID:15465831

    Open questions at the time
    • Direct mitochondrial target of BRE-mediated protection not identified
    • Post-translational modification changes on BRE after receptor stimulation not functionally assigned
  3. 2007 High

    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

    PMID:17704801

    Open questions at the time
    • Whether BRE anti-apoptotic function in vivo operates through XIAP or another mechanism was untested
  4. 2011 High

    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

    PMID:21282113

    Open questions at the time
    • Structural basis of UEV–NBA1 interaction not resolved at atomic level
    • Relative contribution of BRCA1-A versus BRISC to radiation resistance not separated
  5. 2014 High

    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

    PMID:24395041

    Open questions at the time
    • Mechanism by which BRE regulates XIAP mRNA is unknown
    • Whether XIAP regulation is linked to BRE's death receptor binding is untested
  6. 2016 High

    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

    PMID:27001068

    Open questions at the time
    • Whether senescence phenotype is entirely HR-dependent or involves additional BRE functions not resolved
  7. 2017 Medium

    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

    PMID:28436570

    Open questions at the time
    • Whether BRE–p53 interaction is direct or bridged through Mdm2 not definitively resolved
    • Single-lab finding awaiting independent replication
  8. 2018 High

    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

    PMID:29416040

    Open questions at the time
    • 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
  9. 2022 Medium

    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

    PMID:35864959

    Open questions at the time
    • Whether BRE–Hey1 interaction is direct or part of a larger complex is unresolved
    • Single-lab finding in mouse model

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 2
Partners
BABAM1BRCC3FASHEY1TNFRSF1ATP53USP7XIAP
Complex memberships
BRCA1-A complexBRISC complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. Yeast two-hybrid, in vitro pulldown with recombinant proteins, co-immunoprecipitation, NF-κB reporter assay FASEB journal High 9737713
2004 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. Co-immunoprecipitation, siRNA knockdown, overexpression, apoptosis assays, subcellular fractionation The Journal of biological chemistry High 15465831
2011 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. Co-immunoprecipitation, siRNA knockdown, domain mapping, ionizing radiation survival assay, immunofluorescence for BRCA1 foci The Journal of biological chemistry High 21282113
2007 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. Transgenic mouse model, Fas-induced hepatic apoptosis challenge, immunohistochemistry Oncogene High 17704801
2018 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. Insertional mutagenesis screen, co-immunoprecipitation, ubiquitylation assay, cell viability assay, overexpression and knockdown Nature communications High 29416040
2014 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. shRNA knockdown, reconstitution, Western blot, apoptosis assays, qRT-PCR Apoptosis High 24395041
2016 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. BRE knockout mouse fibroblasts, immunofluorescence for γ-H2AX foci and BRCA1 recruitment, SA-β-Gal senescence assay, HR assay Scientific reports High 27001068
2016 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. BRE knockout mouse model, tibialis anterior injury model, time-lapse microscopy, chemotaxis assay, immunofluorescence Biology open Medium 26740569
2017 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. Co-immunoprecipitation, siRNA knockdown, p53 inhibitor rescue, ubiquitination assay, alkaline phosphatase activity, mineralization assay Stem cells Medium 28436570
2022 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. Co-immunoprecipitation, siRNA knockdown, overexpression, transgenic mouse model, LPS-induced calvarial bone resorption model, Nfatc1 reporter assay International journal of biological sciences Medium 35864959
2005 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. Antisense transfection, steroid hormone measurement by RIA, RT-PCR, cAMP assay The Journal of endocrinology Medium 15930177
2020 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. Babam2 knockout mESCs, flow cytometry cell cycle analysis, Western blot for CDC25A/CDK2/p53/Nanog, gamma irradiation and doxorubicin treatment Biomedicines Medium 33050379
2017 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. In ovo electroporation (overexpression/knockdown), in situ hybridization, immunofluorescence, time-lapse imaging in chick embryo Molecular biology of the cell Medium 25568339
2020 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. Overexpression, siRNA knockdown, AKT inhibitor (MK2206) treatment, Western blot, cell cycle analysis, xenograft model Frontiers in oncology Medium 32850455
2006 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. siRNA knockdown, overexpression, comparative 2D proteomics, MALDI-TOF MS, cell proliferation assay Proteomics Medium 16518872
2001 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. RT-PCR, Northern blot, sequence analysis of cDNA isoforms Biochemical and biophysical research communications Medium 11676476

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 BRE modulates granulosa cell death to affect ovarian follicle development and atresia in the mouse. Cell death & disease 64 28333135
1993 Molecular mechanisms of pattern formation by the BRE enhancer of the Ubx gene. The EMBO journal 63 8404855
2011 NBA1/MERIT40 and BRE interaction is required for the integrity of two distinct deubiquitinating enzyme BRCC36-containing complexes. The Journal of biological chemistry 62 21282113
2016 Over-expression of the long non-coding RNA HOTTIP inhibits glioma cell growth by BRE. Journal of experimental & clinical cancer research : CR 47 27733185
1998 BRE: a modulator of TNF-alpha action. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 44 9737713
2004 A death receptor-associated anti-apoptotic protein, BRE, inhibits mitochondrial apoptotic pathway. The Journal of biological chemistry 43 15465831
2007 BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma. Oncogene 37 17704801
2018 BRE/BRCC45 regulates CDC25A stability by recruiting USP7 in response to DNA damage. Nature communications 34 29416040
2011 High BRE expression predicts favorable outcome in adult acute myeloid leukemia, in particular among MLL-AF9-positive patients. Blood 25 21937695
2006 Comparative proteomic analysis reveals a function of the novel death receptor-associated protein BRE in the regulation of prohibitin and p53 expression and proliferation. Proteomics 24 16518872
2008 Comparative proteomic analysis reveals differentially expressed proteins regulated by a potential tumor promoter, BRE, in human esophageal carcinoma cells. Biochemistry and cell biology = Biochimie et biologie cellulaire 23 18756325
2018 Long non-coding RNA BRE-AS1 represses non-small cell lung cancer cell growth and survival via up-regulating NR4A3. Archives of biochemistry and biophysics 22 30227111
2017 Bre Enhances Osteoblastic Differentiation by Promoting the Mdm2-Mediated Degradation of p53. Stem cells (Dayton, Ohio) 22 28436570
2010 High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome. Leukemia 22 20861917
2005 New positive regulators of lin-12 activity in Caenorhabditis elegans include the BRE-5/Brainiac glycosphingolipid biosynthesis enzyme. Genetics 22 16157663
1995 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. Cancer research 22 7493371
2019 LncRNA BRE-AS1 interacts with miR-145-5p to regulate cancer cell proliferation and apoptosis in prostate carcinoma and has early diagnostic values. Bioscience reports 20 30833361
2009 BRE over-expression promotes growth of hepatocellular carcinoma. Biochemical and biophysical research communications 19 20035718
2013 Silencing BRE expression in human umbilical cord perivascular (HUCPV) progenitor cells accelerates osteogenic and chondrogenic differentiation. PloS one 18 23935848
2001 Differential expression of a stress-modulating gene, BRE, in the adrenal gland, in adrenal neoplasia, and in abnormal adrenal tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 18 11259452
2001 Expression of human BRE in multiple isoforms. Biochemical and biophysical research communications 18 11676476
2014 Bacillus thuringiensis Cry6A exhibits nematicidal activity to Caenorhabditis elegans bre mutants and synergistic activity with Cry5B to C. elegans. Letters in applied microbiology 17 24450432
2005 BRE enhances in vivo growth of tumor cells. Biochemical and biophysical research communications 17 15582573
2015 Misexpression of BRE gene in the developing chick neural tube affects neurulation and somitogenesis. Molecular biology of the cell 15 25568339
2016 BRE plays an essential role in preventing replicative and DNA damage-induced premature senescence. Scientific reports 13 27001068
2022 Babam2 negatively regulates osteoclastogenesis by interacting with Hey1 to inhibit Nfatc1 transcription. International journal of biological sciences 12 35864959
2021 SMAD4-induced knockdown of the antisense long noncoding RNA BRE-AS contributes to granulosa cell apoptosis. Molecular therapy. Nucleic acids 12 34458009
2014 Anti-apoptotic protein BRE/BRCC45 attenuates apoptosis through maintaining the expression of caspase inhibitor XIAP in mouse Lewis lung carcinoma D122 cells. Apoptosis : an international journal on programmed cell death 12 24395041
2012 Expression of the BRCA1 complex member BRE predicts disease free survival in breast cancer. Breast cancer research and treatment 12 22706632
2009 Bruno negatively regulates germ cell-less expression in a BRE-independent manner. Mechanisms of development 12 19393317
2016 BRE facilitates skeletal muscle regeneration by promoting satellite cell motility and differentiation. Biology open 11 26740569
1992 An anti-mucin immunotoxin BrE-3-ricin A-chain is potently and selectively toxic to human small-cell lung cancer. International journal of cancer 11 1328073
2021 Long non-coding RNA BRE-AS1 inhibits the proliferation, migration, and invasion of cancer cells in triple-negative breast cancer and predicts patients' survival by downregulating miR-21. BMC cancer 10 34182945
1999 Molecular structure of the amyloid-forming protein kappa I Bre. Journal of biochemistry 9 9990143
2017 Bypassing the Need for the Transcriptional Activator EarA through a Spontaneous Deletion in the BRE Portion of the fla Operon Promoter in Methanococcus maripaludis. Frontiers in microbiology 8 28769898
2010 Differential expression of a novel gene BRE (TNFRSF1A modulator/BRCC45) in response to stress and biological signals. Molecular biology reports 8 19757177
2003 Expression of a conserved mouse stress-modulating gene, Bre: comparison with the human ortholog. DNA and cell biology 7 14565866
2024 LncRNA BRE-AS1 regulates the JAK2/STAT3-mediated inflammatory activation via the miR-30b-5p/SOC3 axis in THP-1 cells. Scientific reports 5 39468152
2023 PDB-BRE: A ligand-protein interaction binding residue extractor based on Protein Data Bank. Proteins 5 37750380
2020 LncRNA BRE-AS1 acts as a tumor suppressor factor in bladder cancer via mediating STAT3. European review for medical and pharmacological sciences 5 32495865
2020 BRE Promotes Esophageal Squamous Cell Carcinoma Growth by Activating AKT Signaling. Frontiers in oncology 5 32850455
2017 C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation. Leukemia 5 28871137
2005 Blocking BRE expression in Leydig cells inhibits steroidogenesis by down-regulating 3beta-hydroxysteroid dehydrogenase. The Journal of endocrinology 5 15930177
2024 Preoperative chemo-CIRT in Re/BRe pancreatic cancer: Insights from a multicenter prospective phase II clinical study (NCT03822936). Tumori 4 39462835
2020 Babam2 Regulates Cell Cycle Progression and Pluripotency in Mouse Embryonic Stem Cells as Revealed by Induced DNA Damage. Biomedicines 4 33050379
1997 Paclitaxel, 5-fluorouracil, and folinic acid in metastatic breast cancer: BRE-26, a phase II trial. Seminars in oncology 4 9071336
2004 Tissue specific expression and sequence analysis of a stress responsive gene Bre in adult golden hamster (Mesocricetus auratus). Cell and tissue research 3 15127289
2024 Clinical value of BRE-AS1 in myocardial infarction and its role in myocardial infarction-induced cardiac muscle cell apoptosis. Scandinavian cardiovascular journal : SCJ 2 38733316
2023 Long non-coding RNA BRE-AS1 inhibits proliferation, migration and invasion of clear cell renal cell carcinoma by downregulating miR-106b-5p. Histology and histopathology 1 37530129
2019 C-terminal BRE inhibits cellular proliferation and increases sensitivity to chemotherapeutic drugs of MLL-AF9 acute myeloid leukemia cells. Leukemia & lymphoma 1 31111759
2016 Molecular Cloning, Expression, and Identification of Bre Genes Involved in Glycosphingolipids Synthesis in Helicoverpa armigera (Lepidoptera: Noctuidae). Journal of economic entomology 1 27190043
2017 [Clinical significance of expressions of EVI1 and BRE genes in 47 acute leukemia patients with MLL rearrangement]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 0 28219220
2013 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. Hemoglobin 0 23470150