{"gene":"BRAT1","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2006,"finding":"BRAT1 (BAAT1) was identified by yeast two-hybrid screening as a novel BRCA1-associated protein that also binds ATM. BRAT1 localizes to DNA double-strand breaks and is required for IR-induced ATM Ser1981 phosphorylation and CHK2 Thr68 phosphorylation. Okadaic acid treatment restored ATM phosphorylation in BRAT1-depleted cells, and purified BRAT1 partially blocked PP2A-mediated dephosphorylation of ATM in vitro, indicating BRAT1 regulates ATM phosphatase activity.","method":"Yeast two-hybrid, siRNA knockdown, in vitro phosphatase inhibition assay with purified BRAT1, okadaic acid rescue experiment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of PP2A inhibition by purified BRAT1, combined with siRNA epistasis and okadaic acid rescue; multiple orthogonal methods in one rigorous study, replicated by subsequent work","pmids":["16452482"],"is_preprint":false},{"year":2010,"finding":"BRAT1 (BAAT1) binds to BRCA1, ATM, DNA-PKcs, and SMC1. Phosphorylation of ATM and DNA-PKcs is greatly reduced in BRAT1-knockdown cells, establishing BRAT1 as a regulator of both kinases in the DNA damage sensing pathway.","method":"Co-immunoprecipitation, siRNA knockdown, Western blot for phosphorylation","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and knockdown with phosphorylation readout; single lab, consistent with prior foundational paper","pmids":["21779444"],"is_preprint":false},{"year":2011,"finding":"BRAT1 binds DNA-PKcs and SMC1 through distinct regions; their binding affinities are altered after treatment with the IR mimetic neocarzinostatin (NCS). BRAT1 depletion by siRNA reduces NCS-induced phosphorylation of DNA-PKcs at Ser2056 and SMC1 at Ser966.","method":"Co-immunoprecipitation, domain-mapping pulldown, siRNA knockdown, Western blot for phosphorylation","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping pulldown plus siRNA epistasis with specific phosphorylation readouts; single lab, two orthogonal methods","pmids":["22977523"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of BRCA1 BRCT domains bound to the BAAT1 phosphopeptide (266-VARpSPVFSS-274) were determined at 2.2 Å resolution. The pSer and Phe+3 anchor the phosphopeptide into the BRCT binding groove; isothermal titration calorimetry showed that residues at positions +1 and +2 contribute significantly to binding affinity.","method":"X-ray crystallography (2.2 Å), isothermal titration calorimetry","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure plus ITC thermodynamic validation; two orthogonal methods establishing binding mode","pmids":["24073851"],"is_preprint":false},{"year":2013,"finding":"Conditional deletion of BRAT1 in mouse embryonic fibroblasts suppressed serum-induced cell cycling and destabilized mTOR and its downstream proteins, indicating BRAT1 is required for stability and serum-induced expression of mTOR.","method":"Conditional gene deletion (MEFs), Western blot for mTOR pathway proteins, cell cycle analysis","journal":"Journal of cancer biology & research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic deletion with defined molecular readout (mTOR stability); single lab, single-method Western blot confirmation","pmids":["25657994"],"is_preprint":false},{"year":2014,"finding":"Stable BRAT1 knockdown in cancer cell lines increased glucose uptake, elevated mitochondrial ROS production, reduced PDH activity, and suppressed basal and induced Akt/Erk kinase activation. Treatment with Akt activator SC79 restored proliferation and reduced mitochondrial ROS, placing BRAT1 upstream of Akt/Erk signaling and mitochondrial homeostasis.","method":"Stable shRNA knockdown, glycolysis assay, mitochondrial ROS measurement (MitoSOX), PDH activity assay, Western blot, SC79 rescue experiment, in vitro/in vivo tumorigenic assays","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (metabolic, signaling, rescue) in multiple cell lines; single lab","pmids":["25070371"],"is_preprint":false},{"year":2015,"finding":"Ndfip1-mediated ubiquitination of BRAT1 by Nedd4 E3 ligases is required for BRAT1 nuclear translocation. Without Ndfip1, BRAT1 failed to enter the nucleus. In neurons following brain injury, increased Ndfip1 expression correlated with nuclear BRAT1 accumulation and maintained ATM phosphorylation.","method":"siRNA knockdown of Ndfip1, confocal microscopy for subcellular localization, Western blot for ubiquitination and ATM phosphorylation, brain injury model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence (ATM phosphorylation), reciprocal knockdown with rescue logic, replicated in cell lines and in vivo neuronal model","pmids":["25631046"],"is_preprint":false},{"year":2019,"finding":"Patient-derived cells carrying a homozygous BRAT1 p.Val62Glu variant showed markedly decreased BRAT1 protein levels. Critically, ATM kinase activation following ionizing radiation was NOT different between patient and control cells, and no differences in PDH phosphorylation or oxygen consumption rates were detected, indicating that loss of BRAT1 function can cause cerebellar ataxia through mechanisms independent of ATM kinase regulation or mitochondrial dysfunction.","method":"Western blotting of patient lymphocytes/fibroblasts, ATM kinase activation assay after IR, PDH phosphorylation assay, oxygen consumption rate measurement (Seahorse)","journal":"Neurology. Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in patient-derived cells; negative result mechanistically informative; single lab","pmids":["31742228"],"is_preprint":false},{"year":2022,"finding":"BRAT1 tightly interacts with INTS9/INTS11 subunits of the Integrator complex. BRAT1 deletion disrupts Integrator functions including 3′-end processing of UsnRNAs and snoRNAs, replication-dependent histone pre-mRNA processing, and expression of protein-coding genes. These Integrator defects were also observed in patient-derived cells from BRAT1-related neurological disease.","method":"Co-immunoprecipitation, RNA-seq, RT-PCR for snRNA/snoRNA processing, patient-derived cell analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP establishing complex, multiple RNA processing readouts (snRNA, snoRNA, histone pre-mRNA, mRNA), validated in patient-derived cells; replicated by independent subsequent work","pmids":["36028512"],"is_preprint":false},{"year":2023,"finding":"BRAT1 forms a trimeric complex with INTS11 and INTS9 in HEK293T and NT2 cells. BRAT1 depletion prevents activation of REST-target neuronal genes by impairing INTS11 recruitment to their promoters, blocking NT2 differentiation into neurons and astrocytes. A disease-causing BRAT1 E522K mutation abolishes its interaction with INTS11/INTS9.","method":"Co-immunoprecipitation, ChIP-seq/ChIP, siRNA/shRNA knockdown, neural differentiation assay, rescue with wild-type vs. mutant BRAT1","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP occupancy, differentiation rescue with mutagenesis; preprint (later published as PMID:38805275)","pmids":["37609215"],"is_preprint":true},{"year":2024,"finding":"BRAT1 forms a distinct trimeric complex with INTS11 and INTS9 of the Integrator complex to activate REST-responsive neuronal genes during differentiation. BRAT1 recruits INTS11 to promoters of critical neuronal genes; BRAT1 depletion causes REST to persist on these promoters, blocking differentiation of NT2 cells into neurons/astrocytes. Reconstitution with wild-type BRAT1 restores differentiation, but a mutant unable to bind INTS11/INTS9 fails to rescue. Loss of Brat1 in mouse ESCs also impairs neuronal differentiation.","method":"Co-immunoprecipitation, ChIP-seq, siRNA/shRNA knockdown, rescue reconstitution with wild-type vs. mutant BRAT1, mouse ESC differentiation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, ChIP, differentiation rescue with mutagenesis, in vivo mouse ESC model) in a single rigorous peer-reviewed study","pmids":["38805275"],"is_preprint":false},{"year":2024,"finding":"BRAT1 depletion in GBM and glioma stem-like cell lines delays DNA double-strand break repair and increases radiation sensitivity in vitro and in vivo. Proteomic/phosphoproteomic analyses show that BRAT1 loss downregulates proteins associated with cell migration and invasion. Treatment with the BRAT1 inhibitor Curcusone D reduces GSC migration and invasion in an ex vivo slice model, synergizing with irradiation.","method":"Stable BRAT1 depletion (shRNA), clonogenic survival/DSB repair assay, in vivo tumor growth assay, proteomics/phosphoproteomics, ex vivo brain slice migration/invasion assay with Curcusone D","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (DSB repair, migration, invasion) in vitro and in vivo with pharmacological validation; single lab","pmids":["39833546"],"is_preprint":false},{"year":2026,"finding":"BRAT1 mutations in patient-derived fibroblasts and lymphoblastoid cells impair U1 snRNA 3′-end processing, leading to nuclear accumulation of unprocessed U1 snRNA transcripts. The magnitude of U1 snRNA misprocessing correlates with clinical severity. This establishes BRAT1's mechanistic contribution to Integrator-dependent RNA processing as the primary pathogenic mechanism.","method":"RT-qPCR, FISH for nuclear U1 snRNA retention in patient-derived cells, Western blot; zebrafish ints11 KO model validation","journal":"Genome medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RT-qPCR, FISH) in patient-derived cells from multiple individuals, with in vivo zebrafish model validation; consistent with and extending prior Integrator interaction work","pmids":["42116163"],"is_preprint":false}],"current_model":"BRAT1 (BRCA1-associated ATM activator 1) functions at multiple levels: it binds BRCA1, ATM, DNA-PKcs, and SMC1 via a BRCA1 BRCT-domain interaction (structurally defined at 2.2 Å), and inhibits PP2A-mediated dephosphorylation of ATM to maintain ATM Ser1981 phosphorylation and downstream CHK2/DNA-PKcs/SMC1 signaling after DNA damage; its nuclear translocation is controlled by Ndfip1-dependent, Nedd4-mediated ubiquitination; it regulates mTOR stability and Akt/Erk signaling to support cell proliferation and mitochondrial homeostasis; and, critically, it forms a trimeric complex with Integrator subunits INTS9/INTS11 to recruit INTS11 to promoters of REST-target neuronal genes, enabling their activation during neuronal differentiation and proper 3′-end processing of U snRNAs—defects in this Integrator-RNA processing function are the primary pathogenic mechanism of BRAT1-associated neurodevelopmental and neurodegenerative disease."},"narrative":{"mechanistic_narrative":"BRAT1 was originally characterized as a DNA damage response regulator that physically associates with BRCA1, ATM, DNA-PKcs, and SMC1 and is required for ionizing-radiation-induced phosphorylation of these kinases and their substrates [PMID:16452482, PMID:21779444, PMID:22977523]. Mechanistically, BRAT1 sustains ATM Ser1981 phosphorylation by inhibiting PP2A-mediated dephosphorylation, an activity reconstituted with purified protein in vitro [PMID:16452482]. Its interaction with BRCA1 occurs through a phosphopeptide (centered on pSer269) docking into the BRCA1 BRCT binding groove, defined crystallographically at 2.2 Å [PMID:24073851], and its nuclear entry depends on Ndfip1-directed, Nedd4-mediated ubiquitination [PMID:25631046]. BRAT1 additionally supports cell proliferation and metabolic homeostasis by stabilizing mTOR and acting upstream of Akt/Erk signaling and mitochondrial function [PMID:25657994, PMID:25070371]. The defining function established for BRAT1 is as a tight binding partner of the Integrator endonuclease subunits INTS9 and INTS11, with which it forms a trimeric complex required for 3′-end processing of U snRNAs, snoRNAs, and replication-dependent histone pre-mRNAs [PMID:36028512]. Through this complex BRAT1 recruits INTS11 to the promoters of REST-target neuronal genes, relieving REST-mediated repression to drive neuronal differentiation; a disease-associated mutation that abolishes INTS11/INTS9 binding fails to rescue differentiation [PMID:38805275]. Defective Integrator-dependent U1 snRNA processing, which produces nuclear accumulation of unprocessed transcripts in proportion to clinical severity, is the primary pathogenic mechanism of BRAT1-associated neurodevelopmental and neurodegenerative disease [PMID:42116163]. Notably, patient cells with ataxia-causing BRAT1 variants retain normal ATM activation and mitochondrial function, indicating the disease mechanism is separable from BRAT1's DNA damage and metabolic roles [PMID:31742228].","teleology":[{"year":2006,"claim":"Established BRAT1's first molecular function: how the DNA damage response sustains ATM activation, answered by showing BRAT1 protects ATM Ser1981 phosphorylation from PP2A.","evidence":"Yeast two-hybrid, siRNA knockdown, in vitro PP2A inhibition with purified BRAT1, and okadaic acid rescue","pmids":["16452482"],"confidence":"High","gaps":["Does not define how BRAT1 physically engages PP2A or ATM at the molecular level","Does not address BRAT1 functions outside DNA damage signaling"]},{"year":2011,"claim":"Broadened BRAT1's kinase regulation by showing it binds and is required for activation of DNA-PKcs and SMC1 as well as ATM, positioning it as a multi-kinase DNA damage regulator.","evidence":"Co-immunoprecipitation, siRNA knockdown, phosphorylation Western blots","pmids":["21779444","22977523"],"confidence":"Medium","gaps":["Binding regions mapped but the structural basis of kinase regulation not resolved","Single-lab phosphorylation readouts"]},{"year":2013,"claim":"Defined the structural basis of the BRAT1–BRCA1 interaction, showing it is a canonical BRCT-phosphopeptide recognition event.","evidence":"X-ray crystallography at 2.2 Å of BRCA1 BRCT bound to the BRAT1 phosphopeptide, plus ITC","pmids":["24073851"],"confidence":"High","gaps":["Does not establish the in vivo kinase responsible for the priming phosphorylation","Does not connect BRCA1 binding to a specific downstream function"]},{"year":2013,"claim":"Extended BRAT1 beyond DNA damage by showing it is required for mTOR stability and serum-induced proliferation.","evidence":"Conditional BRAT1 deletion in MEFs with mTOR pathway Western blots and cell cycle analysis","pmids":["25657994"],"confidence":"Medium","gaps":["Mechanism by which BRAT1 stabilizes mTOR is undefined","Single-method confirmation"]},{"year":2014,"claim":"Connected BRAT1 to metabolic and proliferative signaling, placing it upstream of Akt/Erk and mitochondrial ROS control.","evidence":"Stable shRNA knockdown with glycolysis, MitoSOX, PDH activity assays, and SC79 rescue","pmids":["25070371"],"confidence":"Medium","gaps":["Direct molecular link between BRAT1 and Akt/Erk activation not identified","Single-lab study"]},{"year":2015,"claim":"Resolved how BRAT1 reaches the nucleus, showing Ndfip1/Nedd4-dependent ubiquitination drives its nuclear translocation and sustained ATM signaling.","evidence":"Ndfip1 knockdown, confocal localization, ubiquitination/ATM phosphorylation Western blots, brain injury model","pmids":["25631046"],"confidence":"High","gaps":["Ubiquitin chain type and acceptor sites not mapped","Link between nuclear BRAT1 and its Integrator function not yet made"]},{"year":2019,"claim":"Dissociated the disease mechanism from prior models by showing patient cells with a pathogenic BRAT1 variant retain normal ATM activation and mitochondrial function.","evidence":"Patient-derived cell Western blots, IR-induced ATM kinase assay, PDH phosphorylation, and Seahorse oxygen consumption","pmids":["31742228"],"confidence":"Medium","gaps":["Negative result; does not identify the actual disease-relevant function","Single variant in a single lab"]},{"year":2022,"claim":"Identified the function central to disease by showing BRAT1 interacts with INTS9/INTS11 and is required for Integrator-dependent RNA 3′-end processing.","evidence":"Co-IP, RNA-seq, RT-PCR of snRNA/snoRNA/histone pre-mRNA processing in cell lines and patient-derived cells","pmids":["36028512"],"confidence":"High","gaps":["Does not show how BRAT1 is integrated into Integrator architecture","Does not establish the gene-regulatory consequence for neuronal programs"]},{"year":2024,"claim":"Established the neuronal gene-regulatory output: BRAT1 forms a trimeric complex with INTS11/INTS9 to recruit INTS11 to REST-target promoters and relieve REST repression during differentiation.","evidence":"Co-IP, ChIP-seq, knockdown, wild-type vs. binding-deficient mutant rescue, and mouse ESC differentiation","pmids":["38805275","37609215"],"confidence":"High","gaps":["How the BRAT1-INTS subcomplex is targeted specifically to neuronal promoters is unresolved","Relationship between this trimeric complex and the holo-Integrator complex not defined"]},{"year":2026,"claim":"Defined the primary pathogenic mechanism by linking BRAT1 mutations to impaired U1 snRNA 3′-end processing with severity-correlated nuclear accumulation of unprocessed transcripts.","evidence":"RT-qPCR and FISH in patient-derived cells from multiple individuals, with zebrafish ints11 knockout validation","pmids":["42116163"],"confidence":"High","gaps":["Does not establish how snRNA misprocessing produces the specific neurodegenerative phenotype","Genotype-to-processing-defect relationship across all variants not exhaustive"]},{"year":null,"claim":"It remains unresolved how BRAT1's DNA-damage/ATM-PP2A activity, its mTOR/Akt-metabolic role, and its Integrator-RNA-processing function are mechanistically coordinated within one protein.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural or regulatory model linking the three activities","Unclear which functions are direct versus secondary consequences of BRAT1 loss"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,10]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[8,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10]}],"complexes":["BRAT1-INTS9-INTS11 trimeric complex","Integrator complex"],"partners":["BRCA1","ATM","DNA-PKCS","SMC1","INTS9","INTS11","NDFIP1","PP2A"],"other_free_text":[]}},"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":36,"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. 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BRAT1 localizes to DNA double-strand breaks and is required for IR-induced ATM Ser1981 phosphorylation and CHK2 Thr68 phosphorylation. Okadaic acid treatment restored ATM phosphorylation in BRAT1-depleted cells, and purified BRAT1 partially blocked PP2A-mediated dephosphorylation of ATM in vitro, indicating BRAT1 regulates ATM phosphatase activity.\",\n      \"method\": \"Yeast two-hybrid, siRNA knockdown, in vitro phosphatase inhibition assay with purified BRAT1, okadaic acid rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of PP2A inhibition by purified BRAT1, combined with siRNA epistasis and okadaic acid rescue; multiple orthogonal methods in one rigorous study, replicated by subsequent work\",\n      \"pmids\": [\"16452482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BRAT1 (BAAT1) binds to BRCA1, ATM, DNA-PKcs, and SMC1. Phosphorylation of ATM and DNA-PKcs is greatly reduced in BRAT1-knockdown cells, establishing BRAT1 as a regulator of both kinases in the DNA damage sensing pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Western blot for phosphorylation\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and knockdown with phosphorylation readout; single lab, consistent with prior foundational paper\",\n      \"pmids\": [\"21779444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRAT1 binds DNA-PKcs and SMC1 through distinct regions; their binding affinities are altered after treatment with the IR mimetic neocarzinostatin (NCS). BRAT1 depletion by siRNA reduces NCS-induced phosphorylation of DNA-PKcs at Ser2056 and SMC1 at Ser966.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping pulldown, siRNA knockdown, Western blot for phosphorylation\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping pulldown plus siRNA epistasis with specific phosphorylation readouts; single lab, two orthogonal methods\",\n      \"pmids\": [\"22977523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of BRCA1 BRCT domains bound to the BAAT1 phosphopeptide (266-VARpSPVFSS-274) were determined at 2.2 Å resolution. The pSer and Phe+3 anchor the phosphopeptide into the BRCT binding groove; isothermal titration calorimetry showed that residues at positions +1 and +2 contribute significantly to binding affinity.\",\n      \"method\": \"X-ray crystallography (2.2 Å), isothermal titration calorimetry\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure plus ITC thermodynamic validation; two orthogonal methods establishing binding mode\",\n      \"pmids\": [\"24073851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Conditional deletion of BRAT1 in mouse embryonic fibroblasts suppressed serum-induced cell cycling and destabilized mTOR and its downstream proteins, indicating BRAT1 is required for stability and serum-induced expression of mTOR.\",\n      \"method\": \"Conditional gene deletion (MEFs), Western blot for mTOR pathway proteins, cell cycle analysis\",\n      \"journal\": \"Journal of cancer biology & research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic deletion with defined molecular readout (mTOR stability); single lab, single-method Western blot confirmation\",\n      \"pmids\": [\"25657994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Stable BRAT1 knockdown in cancer cell lines increased glucose uptake, elevated mitochondrial ROS production, reduced PDH activity, and suppressed basal and induced Akt/Erk kinase activation. Treatment with Akt activator SC79 restored proliferation and reduced mitochondrial ROS, placing BRAT1 upstream of Akt/Erk signaling and mitochondrial homeostasis.\",\n      \"method\": \"Stable shRNA knockdown, glycolysis assay, mitochondrial ROS measurement (MitoSOX), PDH activity assay, Western blot, SC79 rescue experiment, in vitro/in vivo tumorigenic assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (metabolic, signaling, rescue) in multiple cell lines; single lab\",\n      \"pmids\": [\"25070371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ndfip1-mediated ubiquitination of BRAT1 by Nedd4 E3 ligases is required for BRAT1 nuclear translocation. Without Ndfip1, BRAT1 failed to enter the nucleus. In neurons following brain injury, increased Ndfip1 expression correlated with nuclear BRAT1 accumulation and maintained ATM phosphorylation.\",\n      \"method\": \"siRNA knockdown of Ndfip1, confocal microscopy for subcellular localization, Western blot for ubiquitination and ATM phosphorylation, brain injury model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence (ATM phosphorylation), reciprocal knockdown with rescue logic, replicated in cell lines and in vivo neuronal model\",\n      \"pmids\": [\"25631046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Patient-derived cells carrying a homozygous BRAT1 p.Val62Glu variant showed markedly decreased BRAT1 protein levels. Critically, ATM kinase activation following ionizing radiation was NOT different between patient and control cells, and no differences in PDH phosphorylation or oxygen consumption rates were detected, indicating that loss of BRAT1 function can cause cerebellar ataxia through mechanisms independent of ATM kinase regulation or mitochondrial dysfunction.\",\n      \"method\": \"Western blotting of patient lymphocytes/fibroblasts, ATM kinase activation assay after IR, PDH phosphorylation assay, oxygen consumption rate measurement (Seahorse)\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in patient-derived cells; negative result mechanistically informative; single lab\",\n      \"pmids\": [\"31742228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BRAT1 tightly interacts with INTS9/INTS11 subunits of the Integrator complex. BRAT1 deletion disrupts Integrator functions including 3′-end processing of UsnRNAs and snoRNAs, replication-dependent histone pre-mRNA processing, and expression of protein-coding genes. These Integrator defects were also observed in patient-derived cells from BRAT1-related neurological disease.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq, RT-PCR for snRNA/snoRNA processing, patient-derived cell analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP establishing complex, multiple RNA processing readouts (snRNA, snoRNA, histone pre-mRNA, mRNA), validated in patient-derived cells; replicated by independent subsequent work\",\n      \"pmids\": [\"36028512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRAT1 forms a trimeric complex with INTS11 and INTS9 in HEK293T and NT2 cells. BRAT1 depletion prevents activation of REST-target neuronal genes by impairing INTS11 recruitment to their promoters, blocking NT2 differentiation into neurons and astrocytes. A disease-causing BRAT1 E522K mutation abolishes its interaction with INTS11/INTS9.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq/ChIP, siRNA/shRNA knockdown, neural differentiation assay, rescue with wild-type vs. mutant BRAT1\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP occupancy, differentiation rescue with mutagenesis; preprint (later published as PMID:38805275)\",\n      \"pmids\": [\"37609215\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRAT1 forms a distinct trimeric complex with INTS11 and INTS9 of the Integrator complex to activate REST-responsive neuronal genes during differentiation. BRAT1 recruits INTS11 to promoters of critical neuronal genes; BRAT1 depletion causes REST to persist on these promoters, blocking differentiation of NT2 cells into neurons/astrocytes. Reconstitution with wild-type BRAT1 restores differentiation, but a mutant unable to bind INTS11/INTS9 fails to rescue. Loss of Brat1 in mouse ESCs also impairs neuronal differentiation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, siRNA/shRNA knockdown, rescue reconstitution with wild-type vs. mutant BRAT1, mouse ESC 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 / Strong — multiple orthogonal methods (Co-IP, ChIP, differentiation rescue with mutagenesis, in vivo mouse ESC model) in a single rigorous peer-reviewed study\",\n      \"pmids\": [\"38805275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRAT1 depletion in GBM and glioma stem-like cell lines delays DNA double-strand break repair and increases radiation sensitivity in vitro and in vivo. Proteomic/phosphoproteomic analyses show that BRAT1 loss downregulates proteins associated with cell migration and invasion. Treatment with the BRAT1 inhibitor Curcusone D reduces GSC migration and invasion in an ex vivo slice model, synergizing with irradiation.\",\n      \"method\": \"Stable BRAT1 depletion (shRNA), clonogenic survival/DSB repair assay, in vivo tumor growth assay, proteomics/phosphoproteomics, ex vivo brain slice migration/invasion assay with Curcusone D\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (DSB repair, migration, invasion) in vitro and in vivo with pharmacological validation; single lab\",\n      \"pmids\": [\"39833546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"BRAT1 mutations in patient-derived fibroblasts and lymphoblastoid cells impair U1 snRNA 3′-end processing, leading to nuclear accumulation of unprocessed U1 snRNA transcripts. The magnitude of U1 snRNA misprocessing correlates with clinical severity. This establishes BRAT1's mechanistic contribution to Integrator-dependent RNA processing as the primary pathogenic mechanism.\",\n      \"method\": \"RT-qPCR, FISH for nuclear U1 snRNA retention in patient-derived cells, Western blot; zebrafish ints11 KO model validation\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RT-qPCR, FISH) in patient-derived cells from multiple individuals, with in vivo zebrafish model validation; consistent with and extending prior Integrator interaction work\",\n      \"pmids\": [\"42116163\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRAT1 (BRCA1-associated ATM activator 1) functions at multiple levels: it binds BRCA1, ATM, DNA-PKcs, and SMC1 via a BRCA1 BRCT-domain interaction (structurally defined at 2.2 Å), and inhibits PP2A-mediated dephosphorylation of ATM to maintain ATM Ser1981 phosphorylation and downstream CHK2/DNA-PKcs/SMC1 signaling after DNA damage; its nuclear translocation is controlled by Ndfip1-dependent, Nedd4-mediated ubiquitination; it regulates mTOR stability and Akt/Erk signaling to support cell proliferation and mitochondrial homeostasis; and, critically, it forms a trimeric complex with Integrator subunits INTS9/INTS11 to recruit INTS11 to promoters of REST-target neuronal genes, enabling their activation during neuronal differentiation and proper 3′-end processing of U snRNAs—defects in this Integrator-RNA processing function are the primary pathogenic mechanism of BRAT1-associated neurodevelopmental and neurodegenerative disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BRAT1 was originally characterized as a DNA damage response regulator that physically associates with BRCA1, ATM, DNA-PKcs, and SMC1 and is required for ionizing-radiation-induced phosphorylation of these kinases and their substrates [#0, #1, #2]. Mechanistically, BRAT1 sustains ATM Ser1981 phosphorylation by inhibiting PP2A-mediated dephosphorylation, an activity reconstituted with purified protein in vitro [#0]. Its interaction with BRCA1 occurs through a phosphopeptide (centered on pSer269) docking into the BRCA1 BRCT binding groove, defined crystallographically at 2.2 Å [#3], and its nuclear entry depends on Ndfip1-directed, Nedd4-mediated ubiquitination [#6]. BRAT1 additionally supports cell proliferation and metabolic homeostasis by stabilizing mTOR and acting upstream of Akt/Erk signaling and mitochondrial function [#4, #5]. The defining function established for BRAT1 is as a tight binding partner of the Integrator endonuclease subunits INTS9 and INTS11, with which it forms a trimeric complex required for 3′-end processing of U snRNAs, snoRNAs, and replication-dependent histone pre-mRNAs [#8]. Through this complex BRAT1 recruits INTS11 to the promoters of REST-target neuronal genes, relieving REST-mediated repression to drive neuronal differentiation; a disease-associated mutation that abolishes INTS11/INTS9 binding fails to rescue differentiation [#10]. Defective Integrator-dependent U1 snRNA processing, which produces nuclear accumulation of unprocessed transcripts in proportion to clinical severity, is the primary pathogenic mechanism of BRAT1-associated neurodevelopmental and neurodegenerative disease [#12]. Notably, patient cells with ataxia-causing BRAT1 variants retain normal ATM activation and mitochondrial function, indicating the disease mechanism is separable from BRAT1's DNA damage and metabolic roles [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established BRAT1's first molecular function: how the DNA damage response sustains ATM activation, answered by showing BRAT1 protects ATM Ser1981 phosphorylation from PP2A.\",\n      \"evidence\": \"Yeast two-hybrid, siRNA knockdown, in vitro PP2A inhibition with purified BRAT1, and okadaic acid rescue\",\n      \"pmids\": [\"16452482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how BRAT1 physically engages PP2A or ATM at the molecular level\", \"Does not address BRAT1 functions outside DNA damage signaling\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Broadened BRAT1's kinase regulation by showing it binds and is required for activation of DNA-PKcs and SMC1 as well as ATM, positioning it as a multi-kinase DNA damage regulator.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, phosphorylation Western blots\",\n      \"pmids\": [\"21779444\", \"22977523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding regions mapped but the structural basis of kinase regulation not resolved\", \"Single-lab phosphorylation readouts\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the structural basis of the BRAT1–BRCA1 interaction, showing it is a canonical BRCT-phosphopeptide recognition event.\",\n      \"evidence\": \"X-ray crystallography at 2.2 Å of BRCA1 BRCT bound to the BRAT1 phosphopeptide, plus ITC\",\n      \"pmids\": [\"24073851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish the in vivo kinase responsible for the priming phosphorylation\", \"Does not connect BRCA1 binding to a specific downstream function\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended BRAT1 beyond DNA damage by showing it is required for mTOR stability and serum-induced proliferation.\",\n      \"evidence\": \"Conditional BRAT1 deletion in MEFs with mTOR pathway Western blots and cell cycle analysis\",\n      \"pmids\": [\"25657994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which BRAT1 stabilizes mTOR is undefined\", \"Single-method confirmation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected BRAT1 to metabolic and proliferative signaling, placing it upstream of Akt/Erk and mitochondrial ROS control.\",\n      \"evidence\": \"Stable shRNA knockdown with glycolysis, MitoSOX, PDH activity assays, and SC79 rescue\",\n      \"pmids\": [\"25070371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between BRAT1 and Akt/Erk activation not identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how BRAT1 reaches the nucleus, showing Ndfip1/Nedd4-dependent ubiquitination drives its nuclear translocation and sustained ATM signaling.\",\n      \"evidence\": \"Ndfip1 knockdown, confocal localization, ubiquitination/ATM phosphorylation Western blots, brain injury model\",\n      \"pmids\": [\"25631046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain type and acceptor sites not mapped\", \"Link between nuclear BRAT1 and its Integrator function not yet made\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissociated the disease mechanism from prior models by showing patient cells with a pathogenic BRAT1 variant retain normal ATM activation and mitochondrial function.\",\n      \"evidence\": \"Patient-derived cell Western blots, IR-induced ATM kinase assay, PDH phosphorylation, and Seahorse oxygen consumption\",\n      \"pmids\": [\"31742228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; does not identify the actual disease-relevant function\", \"Single variant in a single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the function central to disease by showing BRAT1 interacts with INTS9/INTS11 and is required for Integrator-dependent RNA 3′-end processing.\",\n      \"evidence\": \"Co-IP, RNA-seq, RT-PCR of snRNA/snoRNA/histone pre-mRNA processing in cell lines and patient-derived cells\",\n      \"pmids\": [\"36028512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not show how BRAT1 is integrated into Integrator architecture\", \"Does not establish the gene-regulatory consequence for neuronal programs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the neuronal gene-regulatory output: BRAT1 forms a trimeric complex with INTS11/INTS9 to recruit INTS11 to REST-target promoters and relieve REST repression during differentiation.\",\n      \"evidence\": \"Co-IP, ChIP-seq, knockdown, wild-type vs. binding-deficient mutant rescue, and mouse ESC differentiation\",\n      \"pmids\": [\"38805275\", \"37609215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the BRAT1-INTS subcomplex is targeted specifically to neuronal promoters is unresolved\", \"Relationship between this trimeric complex and the holo-Integrator complex not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the primary pathogenic mechanism by linking BRAT1 mutations to impaired U1 snRNA 3′-end processing with severity-correlated nuclear accumulation of unprocessed transcripts.\",\n      \"evidence\": \"RT-qPCR and FISH in patient-derived cells from multiple individuals, with zebrafish ints11 knockout validation\",\n      \"pmids\": [\"42116163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish how snRNA misprocessing produces the specific neurodegenerative phenotype\", \"Genotype-to-processing-defect relationship across all variants not exhaustive\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how BRAT1's DNA-damage/ATM-PP2A activity, its mTOR/Akt-metabolic role, and its Integrator-RNA-processing function are mechanistically coordinated within one protein.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural or regulatory model linking the three activities\", \"Unclear which functions are direct versus secondary consequences of BRAT1 loss\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"BRAT1-INTS9-INTS11 trimeric complex\",\n      \"Integrator complex\"\n    ],\n    \"partners\": [\n      \"BRCA1\",\n      \"ATM\",\n      \"DNA-PKcs\",\n      \"SMC1\",\n      \"INTS9\",\n      \"INTS11\",\n      \"Ndfip1\",\n      \"PP2A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}