{"gene":"BRAT1","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2006,"finding":"BRAT1 (originally named BAAT1) was identified by yeast two-hybrid screening as a BRCA1-binding protein that also binds ATM; it localizes to DNA double-strand breaks and is required for IR-induced phosphorylation of ATM at Ser1981 and CHK2 at Thr68. In vitro, purified BAAT1 partially blocked PP2A-mediated dephosphorylation of ATM, indicating BRAT1 maintains ATM activation by inhibiting its phosphatase.","method":"Yeast two-hybrid screening, siRNA knockdown, in vitro phosphatase assay with purified BAAT1, okadaic acid rescue experiment, immunofluorescence localization to DSBs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including in vitro reconstitution of phosphatase inhibition, siRNA phenotype, and localization; single lab but strong mechanistic depth","pmids":["16452482"],"is_preprint":false},{"year":2010,"finding":"BRAT1 binds to both ATM and DNA-PKcs (as well as SMC1), and depletion of BRAT1 by siRNA reduces phosphorylation of ATM, DNA-PKcs at Ser2056, and SMC1 at Ser966 following DNA damage, indicating BRAT1 globally regulates early DNA damage signaling through multiple PIKK kinases.","method":"Co-immunoprecipitation, siRNA knockdown, western blotting for phosphorylation of DNA-PKcs (Ser2056) and SMC1 (Ser966) after neocarzinostatin treatment; domain mapping by biochemical analysis","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP and KD with defined phosphorylation readouts, single lab, moderate orthogonal support from prior paper","pmids":["21779444"],"is_preprint":false},{"year":2011,"finding":"BRAT1 directly binds to DNA-PKcs and SMC1; multiple regions of BRAT1 mediate these interactions, and binding affinity changes after DNA damage treatment, placing BRAT1 as a regulatory scaffold for DNA-PK signaling.","method":"Co-immunoprecipitation, domain-mapping pulldown, siRNA knockdown with phosphorylation readouts (Ser2056 DNA-PKcs, Ser966 SMC1)","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal co-IP with domain mapping, single lab, replicates prior findings from a different angle","pmids":["22977523"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of the BRCA1 BRCT domains bound to the BAAT1 phosphopeptide (266-VARpSPVFSS-274) determined at 2.2 Å resolution revealed that the pSer and Phe(+3) anchor the peptide in the BRCT binding groove; ITC confirmed that residues at positions +1 and +2 contribute significantly to binding affinity and specificity.","method":"X-ray crystallography (2.2 Å), isothermal titration calorimetry (ITC)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution crystal structure with quantitative ITC validation","pmids":["24073851"],"is_preprint":false},{"year":2013,"finding":"Conditional deletion of BRAT1 in mouse embryonic fibroblasts suppresses serum-induced mTOR stability and expression of downstream mTOR pathway proteins and impairs cell cycle progression, indicating BRAT1 is required for proper PIKK/mTOR signaling cascades.","method":"Conditional gene deletion (MEFs), western blotting for mTOR and downstream targets, cell cycle analysis","journal":"Journal of cancer biology & research","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic KO with specific molecular readout, single lab","pmids":["25657994"],"is_preprint":false},{"year":2014,"finding":"Stable BRAT1 knockdown in cancer cell lines increases glucose uptake and mitochondrial ROS production, reduces PDH activity, and suppresses basal and induced Akt/Erk phosphorylation, establishing that BRAT1 plays roles in mitochondrial metabolism and growth signaling beyond DNA damage response. Treatment with an Akt activator rescued proliferation and reduced mitochondrial ROS, providing epistatic evidence that BRAT1 acts upstream of Akt.","method":"Stable siRNA knockdown cell lines, glucose uptake assay, mitochondrial ROS measurement (MitoSOX), PDH activity assay, Akt/Erk phosphorylation western blot, Akt activator (SC79) rescue, in vitro and in vivo tumorigenesis assays","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal metabolic and signaling assays in stable KD lines with pharmacological rescue; single lab","pmids":["25070371"],"is_preprint":false},{"year":2015,"finding":"Ndfip1 mediates ubiquitination of BRAT1 via Nedd4 E3 ligases, which is required for BRAT1 nuclear translocation in response to genotoxic stress; without Ndfip1, BRAT1 fails to translocate to the nucleus and ATM phosphorylation is not maintained. Following brain injury in neurons, upregulation of Ndfip1 is coupled to nuclear translocation of BRAT1.","method":"Ndfip1 knockdown/overexpression, subcellular fractionation, immunofluorescence, western blotting for BRAT1 localization and phospho-ATM, in vivo brain injury model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, imaging, in vivo model), identifies specific E3 ligase pathway; single lab with strong mechanistic resolution","pmids":["25631046"],"is_preprint":false},{"year":2022,"finding":"BRAT1 tightly interacts with the INTS9/INTS11 subunits of the Integrator complex; BRAT1 deletion disrupts Integrator functions including proper 3′ end processing of UsnRNAs and snoRNAs, replication-dependent histone pre-mRNA processing, and expression of protein-coding genes. These Integrator defects are also evident in patient-derived BRAT1 neurological disease cells.","method":"Co-immunoprecipitation, RNA-seq, snRNA/snoRNA 3′ end processing assays, chromatin immunoprecipitation, BRAT1 knockout cells, patient-derived cell lines","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical and genomic methods, validated in patient cells, published in high-impact journal","pmids":["36028512"],"is_preprint":false},{"year":2024,"finding":"BRAT1 forms a trimeric complex with INTS11 and INTS9 subunits of the Integrator to activate REST-responsive neuronal genes during neuronal differentiation. BRAT1 recruits INTS11 to promoters of key neuronal genes, and its depletion causes persistence of REST at these promoters, blocking differentiation of NT2 cells into neurons and astrocytes. Disease-causing mutations in BRAT1 diminish its interaction with INTS11/INTS9; reconstitution with wild-type but not disease-mutant BRAT1 restores neuronal differentiation in Brat1 KO mouse ESCs.","method":"Co-immunoprecipitation, ChIP-seq, RNA-seq, BRAT1 KO mouse ESC differentiation assay, rescue experiments with WT vs. mutant BRAT1, NT2 differentiation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including genetic KO, rescue with WT/mutant BRAT1, ChIP, disease mutation validation; strong mechanistic resolution","pmids":["38805275"],"is_preprint":false},{"year":2023,"finding":"BRAT1 forms a trimeric complex with INTS11/INTS9 in HEK293T and NT2 cells; BRAT1 depletion prevents activation of REST-target neuronal genes and blocks neural differentiation. The pathogenic E522K mutation in BRAT1 specifically disrupts its interaction with the INTS11/INTS9 heterodimer, linking disease to loss of this complex.","method":"Co-immunoprecipitation in HEK293T and NT2 cells, ChIP, RNA-seq, NT2 differentiation assay, point mutant interaction assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods but preprint; findings later confirmed in peer-reviewed PNAS paper (PMID 38805275)","pmids":["37609215"],"is_preprint":true},{"year":2025,"finding":"Stable depletion of BRAT1 in glioblastoma cell lines delays DNA double-strand break repair and increases radiation sensitivity; proteomic and phosphoproteomic analyses identified BRAT1-dependent regulation of proteins involved in cell migration and invasion. Pharmacological inhibition of BRAT1 with Curcusone D (CurD) reduced glioma stem cell migration and invasion in ex vivo slice cultures and synergized with irradiation to inhibit tumor growth.","method":"Stable shRNA depletion, in vitro and in vivo tumor growth assays, proteomic/phosphoproteomic analysis, γH2AX foci (DSB repair), ex vivo brain slice invasion assay, small-molecule inhibitor (Curcusone D)","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (proteomics, genetic KD, pharmacological inhibition, in vivo), single lab","pmids":["39833546"],"is_preprint":false}],"current_model":"BRAT1 is a multifunctional scaffold protein that (1) binds BRCA1, ATM, DNA-PKcs, and SMC1 to maintain ATM/DNA-PKcs activation after DNA damage by inhibiting PP2A-mediated dephosphorylation; (2) requires Ndfip1-mediated Nedd4 ubiquitination for nuclear translocation in response to genotoxic stress; (3) forms a trimeric complex with Integrator subunits INTS9/INTS11 to recruit INTS11 to promoters of REST-target neuronal genes, thereby activating key neuronal differentiation programs; and (4) influences mTOR/Akt signaling and mitochondrial metabolism, with loss of BRAT1 causing increased mitochondrial ROS and suppressed PDH and Akt/Erk activity."},"narrative":{"teleology":[{"year":2006,"claim":"Identification of BRAT1 as a BRCA1- and ATM-binding protein that localizes to DSBs and is required for ATM activation established its entry point into the DNA damage response, resolving how ATM phosphorylation is sustained after irradiation — via BRAT1-mediated inhibition of PP2A dephosphorylation.","evidence":"Yeast two-hybrid screen, siRNA knockdown, in vitro phosphatase assay with purified BRAT1, okadaic acid rescue","pmids":["16452482"],"confidence":"High","gaps":["Mechanism of PP2A inhibition at the structural level unknown","Whether BRAT1 acts catalytically or stoichiometrically on PP2A not determined","Contribution of BRAT1 to DSB repair outcomes not assessed"]},{"year":2010,"claim":"Extending BRAT1's role beyond ATM, its binding to DNA-PKcs and SMC1 and requirement for their damage-induced phosphorylation established BRAT1 as a general scaffold for multiple PIKK kinases in early DNA damage signaling.","evidence":"Co-immunoprecipitation and siRNA knockdown with phosphorylation readouts for DNA-PKcs Ser2056 and SMC1 Ser966 after neocarzinostatin treatment; domain mapping","pmids":["21779444","22977523"],"confidence":"Medium","gaps":["Direct vs. bridged interactions with DNA-PKcs not fully resolved","How BRAT1 coordinates ATM and DNA-PKcs activities at the same break is unknown","No in vivo validation of DNA-PKcs/SMC1 regulation by BRAT1"]},{"year":2013,"claim":"Atomic-resolution structures of BRCA1 BRCT domains bound to the BRAT1 phosphopeptide defined the molecular basis of the BRCA1–BRAT1 interaction, showing pSer269 and Phe(+3) as key anchoring residues.","evidence":"X-ray crystallography at 2.2 Å resolution, isothermal titration calorimetry","pmids":["24073851"],"confidence":"High","gaps":["Functional consequence of disrupting BRCA1–BRAT1 interaction in cells not tested in this study","Whether phosphorylation of Ser269 is damage-regulated is not established","No full-length structural information for BRAT1"]},{"year":2014,"claim":"Demonstrating functions beyond DNA repair, BRAT1 depletion was shown to increase mitochondrial ROS, suppress PDH activity and Akt/Erk signaling, and impair mTOR stability, with Akt activator rescue placing BRAT1 upstream of Akt in growth signaling.","evidence":"Stable siRNA knockdown, glucose uptake, MitoSOX, PDH activity assay, Akt activator (SC79) rescue; conditional KO MEFs for mTOR analysis","pmids":["25070371","25657994"],"confidence":"Medium","gaps":["Direct molecular mechanism linking BRAT1 to mTOR/Akt is unknown","Whether metabolic phenotypes are separable from DNA damage signaling defects not addressed","No identification of direct metabolic binding partners"]},{"year":2015,"claim":"The discovery that Ndfip1-dependent Nedd4 ubiquitination of BRAT1 is required for its nuclear translocation under genotoxic stress resolved how BRAT1 gains access to nuclear DNA damage sites and connected the ubiquitin pathway to ATM signaling maintenance.","evidence":"Ndfip1 knockdown/overexpression, subcellular fractionation, immunofluorescence, in vivo brain injury model in neurons","pmids":["25631046"],"confidence":"High","gaps":["Specific ubiquitination sites on BRAT1 not mapped","Whether ubiquitin chain type (K48/K63) matters for nuclear import not determined","Nuclear import receptor or mechanism downstream of ubiquitination unknown"]},{"year":2022,"claim":"Identification of BRAT1 as a tight interactor of INTS9/INTS11 revealed a second major function: BRAT1 is required for Integrator-dependent 3′ end processing of UsnRNAs and snoRNAs and for proper expression of protein-coding genes, with defects recapitulated in patient-derived cells.","evidence":"Co-immunoprecipitation, RNA-seq, snRNA/snoRNA processing assays, ChIP, BRAT1 KO cells and patient-derived cell lines","pmids":["36028512"],"confidence":"High","gaps":["Whether BRAT1 functions within the full Integrator complex or a distinct sub-complex is unclear","Structural basis of the BRAT1–INTS9/INTS11 interaction not resolved","Whether RNA processing defects drive the neurological phenotype or are parallel consequences is not established"]},{"year":2024,"claim":"BRAT1 was shown to recruit INTS11 to REST-target neuronal gene promoters during differentiation, and disease-causing mutations (e.g. E522K) that disrupt the BRAT1–INTS11/INTS9 complex block neuronal differentiation, directly linking BRAT1 loss-of-function to neurodevelopmental disease.","evidence":"ChIP-seq, RNA-seq, BRAT1 KO mouse ESC differentiation assay with WT vs. disease-mutant rescue, NT2 differentiation assay","pmids":["38805275"],"confidence":"High","gaps":["How BRAT1 displaces REST from promoters mechanistically is unknown","Whether the DNA damage and Integrator functions of BRAT1 are interdependent in neurons is not tested","No animal model of BRAT1 neurological disease with behavioral phenotyping"]},{"year":2025,"claim":"Proteomic and functional analyses in glioblastoma demonstrated that BRAT1 depletion delays DSB repair and sensitizes to radiation, while pharmacological BRAT1 inhibition suppresses glioma stem cell migration and invasion, establishing BRAT1 as a therapeutic target in brain tumors.","evidence":"Stable shRNA depletion, proteomics/phosphoproteomics, γH2AX foci, ex vivo brain slice invasion assay, Curcusone D inhibitor","pmids":["39833546"],"confidence":"Medium","gaps":["Curcusone D selectivity for BRAT1 versus off-target effects not fully characterized","Whether anti-invasion effects are mediated through Integrator or DDR functions is unknown","No clinical validation"]},{"year":null,"claim":"Key open questions include: (1) how the DNA damage scaffold and Integrator/neuronal differentiation functions of BRAT1 are coordinated or separated; (2) the structural basis of the BRAT1–INTS9/INTS11 trimeric complex; (3) the direct molecular mechanism connecting BRAT1 to Akt/mTOR and mitochondrial metabolism; and (4) whether BRAT1 has distinct functions in different cell types.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length structure of BRAT1 or its complexes","Separation-of-function mutations distinguishing DDR from Integrator roles not generated","In vivo animal models of BRAT1 disease with mechanistic characterization are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,6,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1,2,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7]}],"complexes":["BRAT1–INTS9–INTS11 trimeric complex"],"partners":["BRCA1","ATM","PRKDC","SMC1A","INTS11","INTS9","NDFIP1","NEDD4"],"other_free_text":[]},"mechanistic_narrative":"BRAT1 is a scaffold protein that integrates DNA damage signaling, RNA processing, and neuronal differentiation programs. It binds BRCA1, ATM, DNA-PKcs, and SMC1 at DNA double-strand breaks and maintains PIKK kinase activation by inhibiting PP2A-mediated dephosphorylation; its nuclear translocation under genotoxic stress requires Ndfip1/Nedd4-dependent ubiquitination [PMID:16452482, PMID:25631046]. BRAT1 forms a trimeric complex with Integrator subunits INTS9 and INTS11, recruiting INTS11 to promoters of REST-target neuronal genes to activate neuronal differentiation; disease-causing mutations that disrupt this interaction block neural differentiation, establishing BRAT1 loss-of-function as a cause of neurodevelopmental disease [PMID:36028512, PMID:38805275]. BRAT1 also influences mitochondrial metabolism and Akt/mTOR signaling, as its depletion increases mitochondrial ROS, suppresses PDH activity, and reduces Akt/Erk phosphorylation [PMID:25070371, PMID:25657994]."},"prefetch_data":{"uniprot":{"accession":"Q6PJG6","full_name":"Integrator complex assembly factor BRAT1","aliases":["BRCA1-associated ATM activator 1","BRCA1-associated protein required for ATM activation protein 1"],"length_aa":821,"mass_kda":88.1,"function":"Component of a multiprotein complex required for the assembly of the RNA endonuclease module of the integrator complex (PubMed:39032489, PubMed:39032490). Associates with INTS9 and INTS11 in the cytoplasm and blocks the active site of INTS11 to inhibit the endonuclease activity of INTS11 before formation of the full integrator complex (PubMed:39032489, PubMed:39032490). Following dissociation of WDR73 of the complex, BRAT1 facilitates the nuclear import of the INTS9-INTS11 heterodimer (PubMed:39032489). In the nucleus, INTS4 is integrated to the INTS9-INTS11 heterodimer and BRAT1 is released from the mature RNA endonuclease module by inositol hexakisphosphate (InsP6) (PubMed:39032489). BRAT1 is also involved in DNA damage response; activates kinases ATM, SMC1A and PRKDC by modulating their phosphorylation status following ionizing radiation (IR) stress (PubMed:16452482, PubMed:22977523). Plays a role in regulating mitochondrial function and cell proliferation (PubMed:25070371). Required for protein stability of MTOR and MTOR-related proteins, and cell cycle progress by growth factors (PubMed:25657994)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6PJG6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BRAT1","classification":"Not Classified","n_dependent_lines":563,"n_total_lines":1208,"dependency_fraction":0.46605960264900664},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BRAT1","total_profiled":1310},"omim":[{"mim_id":"618056","title":"NEURODEVELOPMENTAL DISORDER WITH CEREBELLAR ATROPHY AND WITH OR WITHOUT SEIZURES; NEDCAS","url":"https://www.omim.org/entry/618056"},{"mim_id":"614506","title":"BRCA1-ASSOCIATED ATM ACTIVATOR 1; BRAT1","url":"https://www.omim.org/entry/614506"},{"mim_id":"614498","title":"RIGIDITY AND MULTIFOCAL SEIZURE SYNDROME, LETHAL NEONATAL; RMFSL","url":"https://www.omim.org/entry/614498"},{"mim_id":"113705","title":"BRCA1 DNA REPAIR-ASSOCIATED PROTEIN; BRCA1","url":"https://www.omim.org/entry/113705"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BRAT1"},"hgnc":{"alias_symbol":["MGC22916"],"prev_symbol":["C7orf27","BAAT1"]},"alphafold":{"accession":"Q6PJG6","domains":[{"cath_id":"-","chopping":"521-581_591-630","consensus_level":"medium","plddt":92.8818,"start":521,"end":630},{"cath_id":"-","chopping":"631-671_686-735_755-800","consensus_level":"medium","plddt":82.6734,"start":631,"end":800},{"cath_id":"1.25.40","chopping":"2-144","consensus_level":"medium","plddt":90.4289,"start":2,"end":144}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PJG6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PJG6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PJG6-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BRAT1","jax_strain_url":"https://www.jax.org/strain/search?query=BRAT1"},"sequence":{"accession":"Q6PJG6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PJG6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PJG6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PJG6"}},"corpus_meta":[{"pmid":"25070371","id":"PMC_25070371","title":"BRAT1 deficiency causes increased glucose metabolism and mitochondrial malfunction.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25070371","citation_count":49,"is_preprint":false},{"pmid":"16452482","id":"PMC_16452482","title":"ATM activation by ionizing radiation requires BRCA1-associated BAAT1.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16452482","citation_count":49,"is_preprint":false},{"pmid":"27282546","id":"PMC_27282546","title":"BRAT1 mutations present with a spectrum of clinical severity.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27282546","citation_count":39,"is_preprint":false},{"pmid":"25319849","id":"PMC_25319849","title":"Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly.","date":"2014","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25319849","citation_count":35,"is_preprint":false},{"pmid":"25631046","id":"PMC_25631046","title":"Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination and nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during the DNA damage response.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25631046","citation_count":28,"is_preprint":false},{"pmid":"25500575","id":"PMC_25500575","title":"Lethal neonatal rigidity and multifocal seizure syndrome--report of another family with a BRAT1 mutation.","date":"2014","source":"European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society","url":"https://pubmed.ncbi.nlm.nih.gov/25500575","citation_count":27,"is_preprint":false},{"pmid":"27282648","id":"PMC_27282648","title":"BRAT1 mutations are associated with infantile epileptic encephalopathy, mitochondrial dysfunction, and survival into childhood.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27282648","citation_count":26,"is_preprint":false},{"pmid":"26494257","id":"PMC_26494257","title":"BRAT1-related disease--identification of a patient without early lethality.","date":"2015","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/26494257","citation_count":25,"is_preprint":false},{"pmid":"21779444","id":"PMC_21779444","title":"Regulation of ATM/DNA-PKcs Phosphorylation by BRCA1-Associated BAAT1.","date":"2010","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21779444","citation_count":20,"is_preprint":false},{"pmid":"36028512","id":"PMC_36028512","title":"BRAT1 links Integrator and defective RNA processing with neurodegeneration.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36028512","citation_count":19,"is_preprint":false},{"pmid":"27273316","id":"PMC_27273316","title":"The Arabidopsis acetylated histone-binding protein BRAT1 forms a complex with BRP1 and prevents transcriptional silencing.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27273316","citation_count":19,"is_preprint":false},{"pmid":"26535877","id":"PMC_26535877","title":"Early-Onset Severe Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of Causes.","date":"2015","source":"Neuropediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/26535877","citation_count":17,"is_preprint":false},{"pmid":"30346566","id":"PMC_30346566","title":"BRAT1 Mutation: The First Reported Case of Chinese Origin and Review of the Literature.","date":"2018","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/30346566","citation_count":16,"is_preprint":false},{"pmid":"22977523","id":"PMC_22977523","title":"Functional interaction of BRCA1/ATM-associated BAAT1 with the DNA-PK catalytic subunit.","date":"2011","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22977523","citation_count":16,"is_preprint":false},{"pmid":"31742228","id":"PMC_31742228","title":"Homozygous pathogenic variant in BRAT1 associated with nonprogressive cerebellar ataxia.","date":"2019","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31742228","citation_count":15,"is_preprint":false},{"pmid":"25657994","id":"PMC_25657994","title":"The Potential Role of BRCA1-Associated ATM Activator-1 (BRAT1) in Regulation of mTOR.","date":"2013","source":"Journal of cancer biology & research","url":"https://pubmed.ncbi.nlm.nih.gov/25657994","citation_count":15,"is_preprint":false},{"pmid":"24073851","id":"PMC_24073851","title":"Structural basis for the BRCA1 BRCT interaction with the proteins ATRIP and BAAT1.","date":"2013","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24073851","citation_count":13,"is_preprint":false},{"pmid":"28752061","id":"PMC_28752061","title":"Lethal neonatal rigidity and multifocal seizure syndrome with a new mutation in BRAT1.","date":"2017","source":"Epilepsy & behavior case reports","url":"https://pubmed.ncbi.nlm.nih.gov/28752061","citation_count":13,"is_preprint":false},{"pmid":"34747546","id":"PMC_34747546","title":"Clinical variability at the mild end of BRAT1-related spectrum: Evidence from two families with genotype-phenotype discordance.","date":"2021","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/34747546","citation_count":12,"is_preprint":false},{"pmid":"33040300","id":"PMC_33040300","title":"An intronic variant in BRAT1 creates a cryptic splice site, causing epileptic encephalopathy without prominent rigidity.","date":"2020","source":"Acta neurologica Belgica","url":"https://pubmed.ncbi.nlm.nih.gov/33040300","citation_count":12,"is_preprint":false},{"pmid":"38805275","id":"PMC_38805275","title":"Neuronal differentiation requires BRAT1 complex to remove REST from chromatin.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38805275","citation_count":11,"is_preprint":false},{"pmid":"30786674","id":"PMC_30786674","title":"Clinico-pathological correlation in case of BRAT1 mutation.","date":"2018","source":"Folia neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/30786674","citation_count":11,"is_preprint":false},{"pmid":"33790413","id":"PMC_33790413","title":"Novel variant in BRAT1 with the lethal neonatal rigidity and multifocal seizure syndrome.","date":"2021","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/33790413","citation_count":9,"is_preprint":false},{"pmid":"36335521","id":"PMC_36335521","title":"Involvement of B-aat1 and Cbs in regulating mantle pigmentation in the Pacific oyster (Crassostrea gigas).","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36335521","citation_count":9,"is_preprint":false},{"pmid":"32345087","id":"PMC_32345087","title":"A novel pathogenic variant of BRAT1 gene causes rigidity and multifocal seizure syndrome, lethal neonatal.","date":"2020","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32345087","citation_count":8,"is_preprint":false},{"pmid":"36367347","id":"PMC_36367347","title":"Compound heterozygous loss-of-function variants in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome.","date":"2022","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36367347","citation_count":6,"is_preprint":false},{"pmid":"28635423","id":"PMC_28635423","title":"Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1.","date":"2017","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28635423","citation_count":6,"is_preprint":false},{"pmid":"35360849","id":"PMC_35360849","title":"Novel Biallelic Variant in the BRAT1 Gene Caused Nonprogressive Cerebellar Ataxia Syndrome.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35360849","citation_count":5,"is_preprint":false},{"pmid":"37609215","id":"PMC_37609215","title":"BRAT1 associates with INTS11/INTS9 heterodimer to regulate key neurodevelopmental genes.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37609215","citation_count":5,"is_preprint":false},{"pmid":"35656505","id":"PMC_35656505","title":"Serum Anti-BRAT1 is a Common Molecular Biomarker for Gastrointestinal Cancers and Atherosclerosis.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35656505","citation_count":4,"is_preprint":false},{"pmid":"39833546","id":"PMC_39833546","title":"BRAT1 - a new therapeutic target for glioblastoma.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39833546","citation_count":3,"is_preprint":false},{"pmid":"39586739","id":"PMC_39586739","title":"Novel BRAT1 Deep Intronic Variant Affects Splicing Regulatory Elements Causing Cerebellar Hypoplasia Syndrome: Genotypic and Phenotypic Expansion.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39586739","citation_count":2,"is_preprint":false},{"pmid":"38607605","id":"PMC_38607605","title":"Clinical characteristics of BRAT1-related disease: a systematic literature review.","date":"2024","source":"Acta neurologica Belgica","url":"https://pubmed.ncbi.nlm.nih.gov/38607605","citation_count":1,"is_preprint":false},{"pmid":"39188779","id":"PMC_39188779","title":"Novel BRAT1 variant associated with neurodevelopmental disorder with cerebellar atrophy and seizure: Case report and a literature review.","date":"2024","source":"Epilepsy & behavior reports","url":"https://pubmed.ncbi.nlm.nih.gov/39188779","citation_count":1,"is_preprint":false},{"pmid":"37009381","id":"PMC_37009381","title":"BRAT1 Mutation Retrospective Diagnosis: A Case Report.","date":"2023","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/37009381","citation_count":1,"is_preprint":false},{"pmid":"41737239","id":"PMC_41737239","title":"BRAT1 gene compound heterozygous mutations causing lethal neonatal rigidity and multifocal seizure syndrome: a case report.","date":"2026","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/41737239","citation_count":0,"is_preprint":false},{"pmid":"38019165","id":"PMC_38019165","title":"BRAT1-Associated Leukodystrophy Exacerbated by Classic Hodgkin Lymphoma-Directed Therapy.","date":"2024","source":"The neurologist","url":"https://pubmed.ncbi.nlm.nih.gov/38019165","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18188,"output_tokens":3093,"usd":0.050479},"stage2":{"model":"claude-opus-4-6","input_tokens":6445,"output_tokens":2712,"usd":0.150037},"total_usd":0.200516,"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\": 2006,\n      \"finding\": \"BRAT1 (originally named BAAT1) was identified by yeast two-hybrid screening as a BRCA1-binding protein that also binds ATM; it localizes to DNA double-strand breaks and is required for IR-induced phosphorylation of ATM at Ser1981 and CHK2 at Thr68. In vitro, purified BAAT1 partially blocked PP2A-mediated dephosphorylation of ATM, indicating BRAT1 maintains ATM activation by inhibiting its phosphatase.\",\n      \"method\": \"Yeast two-hybrid screening, siRNA knockdown, in vitro phosphatase assay with purified BAAT1, okadaic acid rescue experiment, immunofluorescence localization to DSBs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including in vitro reconstitution of phosphatase inhibition, siRNA phenotype, and localization; single lab but strong mechanistic depth\",\n      \"pmids\": [\"16452482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BRAT1 binds to both ATM and DNA-PKcs (as well as SMC1), and depletion of BRAT1 by siRNA reduces phosphorylation of ATM, DNA-PKcs at Ser2056, and SMC1 at Ser966 following DNA damage, indicating BRAT1 globally regulates early DNA damage signaling through multiple PIKK kinases.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, western blotting for phosphorylation of DNA-PKcs (Ser2056) and SMC1 (Ser966) after neocarzinostatin treatment; domain mapping by biochemical analysis\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP and KD with defined phosphorylation readouts, single lab, moderate orthogonal support from prior paper\",\n      \"pmids\": [\"21779444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRAT1 directly binds to DNA-PKcs and SMC1; multiple regions of BRAT1 mediate these interactions, and binding affinity changes after DNA damage treatment, placing BRAT1 as a regulatory scaffold for DNA-PK signaling.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping pulldown, siRNA knockdown with phosphorylation readouts (Ser2056 DNA-PKcs, Ser966 SMC1)\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal co-IP with domain mapping, single lab, replicates prior findings from a different angle\",\n      \"pmids\": [\"22977523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of the BRCA1 BRCT domains bound to the BAAT1 phosphopeptide (266-VARpSPVFSS-274) determined at 2.2 Å resolution revealed that the pSer and Phe(+3) anchor the peptide in the BRCT binding groove; ITC confirmed that residues at positions +1 and +2 contribute significantly to binding affinity and specificity.\",\n      \"method\": \"X-ray crystallography (2.2 Å), isothermal titration calorimetry (ITC)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution crystal structure with quantitative ITC validation\",\n      \"pmids\": [\"24073851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Conditional deletion of BRAT1 in mouse embryonic fibroblasts suppresses serum-induced mTOR stability and expression of downstream mTOR pathway proteins and impairs cell cycle progression, indicating BRAT1 is required for proper PIKK/mTOR signaling cascades.\",\n      \"method\": \"Conditional gene deletion (MEFs), western blotting for mTOR and downstream targets, cell cycle analysis\",\n      \"journal\": \"Journal of cancer biology & research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with specific molecular readout, single lab\",\n      \"pmids\": [\"25657994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Stable BRAT1 knockdown in cancer cell lines increases glucose uptake and mitochondrial ROS production, reduces PDH activity, and suppresses basal and induced Akt/Erk phosphorylation, establishing that BRAT1 plays roles in mitochondrial metabolism and growth signaling beyond DNA damage response. Treatment with an Akt activator rescued proliferation and reduced mitochondrial ROS, providing epistatic evidence that BRAT1 acts upstream of Akt.\",\n      \"method\": \"Stable siRNA knockdown cell lines, glucose uptake assay, mitochondrial ROS measurement (MitoSOX), PDH activity assay, Akt/Erk phosphorylation western blot, Akt activator (SC79) rescue, in vitro and in vivo tumorigenesis assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal metabolic and signaling assays in stable KD lines with pharmacological rescue; single lab\",\n      \"pmids\": [\"25070371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ndfip1 mediates ubiquitination of BRAT1 via Nedd4 E3 ligases, which is required for BRAT1 nuclear translocation in response to genotoxic stress; without Ndfip1, BRAT1 fails to translocate to the nucleus and ATM phosphorylation is not maintained. Following brain injury in neurons, upregulation of Ndfip1 is coupled to nuclear translocation of BRAT1.\",\n      \"method\": \"Ndfip1 knockdown/overexpression, subcellular fractionation, immunofluorescence, western blotting for BRAT1 localization and phospho-ATM, in vivo brain injury model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, imaging, in vivo model), identifies specific E3 ligase pathway; single lab with strong mechanistic resolution\",\n      \"pmids\": [\"25631046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BRAT1 tightly interacts with the INTS9/INTS11 subunits of the Integrator complex; BRAT1 deletion disrupts Integrator functions including proper 3′ end processing of UsnRNAs and snoRNAs, replication-dependent histone pre-mRNA processing, and expression of protein-coding genes. These Integrator defects are also evident in patient-derived BRAT1 neurological disease cells.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq, snRNA/snoRNA 3′ end processing assays, chromatin immunoprecipitation, BRAT1 knockout cells, patient-derived cell lines\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical and genomic methods, validated in patient cells, published in high-impact journal\",\n      \"pmids\": [\"36028512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRAT1 forms a trimeric complex with INTS11 and INTS9 subunits of the Integrator to activate REST-responsive neuronal genes during neuronal differentiation. BRAT1 recruits INTS11 to promoters of key neuronal genes, and its depletion causes persistence of REST at these promoters, blocking differentiation of NT2 cells into neurons and astrocytes. Disease-causing mutations in BRAT1 diminish its interaction with INTS11/INTS9; reconstitution with wild-type but not disease-mutant BRAT1 restores neuronal differentiation in Brat1 KO mouse ESCs.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, RNA-seq, BRAT1 KO mouse ESC differentiation assay, rescue experiments with WT vs. mutant BRAT1, NT2 differentiation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including genetic KO, rescue with WT/mutant BRAT1, ChIP, disease mutation validation; strong mechanistic resolution\",\n      \"pmids\": [\"38805275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRAT1 forms a trimeric complex with INTS11/INTS9 in HEK293T and NT2 cells; BRAT1 depletion prevents activation of REST-target neuronal genes and blocks neural differentiation. The pathogenic E522K mutation in BRAT1 specifically disrupts its interaction with the INTS11/INTS9 heterodimer, linking disease to loss of this complex.\",\n      \"method\": \"Co-immunoprecipitation in HEK293T and NT2 cells, ChIP, RNA-seq, NT2 differentiation assay, point mutant interaction assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods but preprint; findings later confirmed in peer-reviewed PNAS paper (PMID 38805275)\",\n      \"pmids\": [\"37609215\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Stable depletion of BRAT1 in glioblastoma cell lines delays DNA double-strand break repair and increases radiation sensitivity; proteomic and phosphoproteomic analyses identified BRAT1-dependent regulation of proteins involved in cell migration and invasion. Pharmacological inhibition of BRAT1 with Curcusone D (CurD) reduced glioma stem cell migration and invasion in ex vivo slice cultures and synergized with irradiation to inhibit tumor growth.\",\n      \"method\": \"Stable shRNA depletion, in vitro and in vivo tumor growth assays, proteomic/phosphoproteomic analysis, γH2AX foci (DSB repair), ex vivo brain slice invasion assay, small-molecule inhibitor (Curcusone D)\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (proteomics, genetic KD, pharmacological inhibition, in vivo), single lab\",\n      \"pmids\": [\"39833546\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRAT1 is a multifunctional scaffold protein that (1) binds BRCA1, ATM, DNA-PKcs, and SMC1 to maintain ATM/DNA-PKcs activation after DNA damage by inhibiting PP2A-mediated dephosphorylation; (2) requires Ndfip1-mediated Nedd4 ubiquitination for nuclear translocation in response to genotoxic stress; (3) forms a trimeric complex with Integrator subunits INTS9/INTS11 to recruit INTS11 to promoters of REST-target neuronal genes, thereby activating key neuronal differentiation programs; and (4) influences mTOR/Akt signaling and mitochondrial metabolism, with loss of BRAT1 causing increased mitochondrial ROS and suppressed PDH and Akt/Erk activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BRAT1 is a scaffold protein that integrates DNA damage signaling, RNA processing, and neuronal differentiation programs. It binds BRCA1, ATM, DNA-PKcs, and SMC1 at DNA double-strand breaks and maintains PIKK kinase activation by inhibiting PP2A-mediated dephosphorylation; its nuclear translocation under genotoxic stress requires Ndfip1/Nedd4-dependent ubiquitination [PMID:16452482, PMID:25631046]. BRAT1 forms a trimeric complex with Integrator subunits INTS9 and INTS11, recruiting INTS11 to promoters of REST-target neuronal genes to activate neuronal differentiation; disease-causing mutations that disrupt this interaction block neural differentiation, establishing BRAT1 loss-of-function as a cause of neurodevelopmental disease [PMID:36028512, PMID:38805275]. BRAT1 also influences mitochondrial metabolism and Akt/mTOR signaling, as its depletion increases mitochondrial ROS, suppresses PDH activity, and reduces Akt/Erk phosphorylation [PMID:25070371, PMID:25657994].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of BRAT1 as a BRCA1- and ATM-binding protein that localizes to DSBs and is required for ATM activation established its entry point into the DNA damage response, resolving how ATM phosphorylation is sustained after irradiation — via BRAT1-mediated inhibition of PP2A dephosphorylation.\",\n      \"evidence\": \"Yeast two-hybrid screen, siRNA knockdown, in vitro phosphatase assay with purified BRAT1, okadaic acid rescue\",\n      \"pmids\": [\"16452482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PP2A inhibition at the structural level unknown\", \"Whether BRAT1 acts catalytically or stoichiometrically on PP2A not determined\", \"Contribution of BRAT1 to DSB repair outcomes not assessed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extending BRAT1's role beyond ATM, its binding to DNA-PKcs and SMC1 and requirement for their damage-induced phosphorylation established BRAT1 as a general scaffold for multiple PIKK kinases in early DNA damage signaling.\",\n      \"evidence\": \"Co-immunoprecipitation and siRNA knockdown with phosphorylation readouts for DNA-PKcs Ser2056 and SMC1 Ser966 after neocarzinostatin treatment; domain mapping\",\n      \"pmids\": [\"21779444\", \"22977523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. bridged interactions with DNA-PKcs not fully resolved\", \"How BRAT1 coordinates ATM and DNA-PKcs activities at the same break is unknown\", \"No in vivo validation of DNA-PKcs/SMC1 regulation by BRAT1\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Atomic-resolution structures of BRCA1 BRCT domains bound to the BRAT1 phosphopeptide defined the molecular basis of the BRCA1–BRAT1 interaction, showing pSer269 and Phe(+3) as key anchoring residues.\",\n      \"evidence\": \"X-ray crystallography at 2.2 Å resolution, isothermal titration calorimetry\",\n      \"pmids\": [\"24073851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of disrupting BRCA1–BRAT1 interaction in cells not tested in this study\", \"Whether phosphorylation of Ser269 is damage-regulated is not established\", \"No full-length structural information for BRAT1\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating functions beyond DNA repair, BRAT1 depletion was shown to increase mitochondrial ROS, suppress PDH activity and Akt/Erk signaling, and impair mTOR stability, with Akt activator rescue placing BRAT1 upstream of Akt in growth signaling.\",\n      \"evidence\": \"Stable siRNA knockdown, glucose uptake, MitoSOX, PDH activity assay, Akt activator (SC79) rescue; conditional KO MEFs for mTOR analysis\",\n      \"pmids\": [\"25070371\", \"25657994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism linking BRAT1 to mTOR/Akt is unknown\", \"Whether metabolic phenotypes are separable from DNA damage signaling defects not addressed\", \"No identification of direct metabolic binding partners\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The discovery that Ndfip1-dependent Nedd4 ubiquitination of BRAT1 is required for its nuclear translocation under genotoxic stress resolved how BRAT1 gains access to nuclear DNA damage sites and connected the ubiquitin pathway to ATM signaling maintenance.\",\n      \"evidence\": \"Ndfip1 knockdown/overexpression, subcellular fractionation, immunofluorescence, in vivo brain injury model in neurons\",\n      \"pmids\": [\"25631046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ubiquitination sites on BRAT1 not mapped\", \"Whether ubiquitin chain type (K48/K63) matters for nuclear import not determined\", \"Nuclear import receptor or mechanism downstream of ubiquitination unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of BRAT1 as a tight interactor of INTS9/INTS11 revealed a second major function: BRAT1 is required for Integrator-dependent 3′ end processing of UsnRNAs and snoRNAs and for proper expression of protein-coding genes, with defects recapitulated in patient-derived cells.\",\n      \"evidence\": \"Co-immunoprecipitation, RNA-seq, snRNA/snoRNA processing assays, ChIP, BRAT1 KO cells and patient-derived cell lines\",\n      \"pmids\": [\"36028512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRAT1 functions within the full Integrator complex or a distinct sub-complex is unclear\", \"Structural basis of the BRAT1–INTS9/INTS11 interaction not resolved\", \"Whether RNA processing defects drive the neurological phenotype or are parallel consequences is not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"BRAT1 was shown to recruit INTS11 to REST-target neuronal gene promoters during differentiation, and disease-causing mutations (e.g. E522K) that disrupt the BRAT1–INTS11/INTS9 complex block neuronal differentiation, directly linking BRAT1 loss-of-function to neurodevelopmental disease.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, BRAT1 KO mouse ESC differentiation assay with WT vs. disease-mutant rescue, NT2 differentiation assay\",\n      \"pmids\": [\"38805275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BRAT1 displaces REST from promoters mechanistically is unknown\", \"Whether the DNA damage and Integrator functions of BRAT1 are interdependent in neurons is not tested\", \"No animal model of BRAT1 neurological disease with behavioral phenotyping\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proteomic and functional analyses in glioblastoma demonstrated that BRAT1 depletion delays DSB repair and sensitizes to radiation, while pharmacological BRAT1 inhibition suppresses glioma stem cell migration and invasion, establishing BRAT1 as a therapeutic target in brain tumors.\",\n      \"evidence\": \"Stable shRNA depletion, proteomics/phosphoproteomics, γH2AX foci, ex vivo brain slice invasion assay, Curcusone D inhibitor\",\n      \"pmids\": [\"39833546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Curcusone D selectivity for BRAT1 versus off-target effects not fully characterized\", \"Whether anti-invasion effects are mediated through Integrator or DDR functions is unknown\", \"No clinical validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: (1) how the DNA damage scaffold and Integrator/neuronal differentiation functions of BRAT1 are coordinated or separated; (2) the structural basis of the BRAT1–INTS9/INTS11 trimeric complex; (3) the direct molecular mechanism connecting BRAT1 to Akt/mTOR and mitochondrial metabolism; and (4) whether BRAT1 has distinct functions in different cell types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length structure of BRAT1 or its complexes\", \"Separation-of-function mutations distinguishing DDR from Integrator roles not generated\", \"In vivo animal models of BRAT1 disease with mechanistic characterization are lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1, 2, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"BRAT1–INTS9–INTS11 trimeric complex\"\n    ],\n    \"partners\": [\n      \"BRCA1\",\n      \"ATM\",\n      \"PRKDC\",\n      \"SMC1A\",\n      \"INTS11\",\n      \"INTS9\",\n      \"NDFIP1\",\n      \"NEDD4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}