Affinage

BRAT1

Integrator complex assembly factor BRAT1 · UniProt Q6PJG6

Length
821 aa
Mass
88.1 kDa
Annotated
2026-06-09
37 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2006 High

    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

    PMID:16452482

    Open questions at the time
    • Does not define how BRAT1 physically engages PP2A or ATM at the molecular level
    • Does not address BRAT1 functions outside DNA damage signaling
  2. 2011 Medium

    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

    PMID:21779444 PMID:22977523

    Open questions at the time
    • Binding regions mapped but the structural basis of kinase regulation not resolved
    • Single-lab phosphorylation readouts
  3. 2013 High

    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

    PMID:24073851

    Open questions at the time
    • Does not establish the in vivo kinase responsible for the priming phosphorylation
    • Does not connect BRCA1 binding to a specific downstream function
  4. 2013 Medium

    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

    PMID:25657994

    Open questions at the time
    • Mechanism by which BRAT1 stabilizes mTOR is undefined
    • Single-method confirmation
  5. 2014 Medium

    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

    PMID:25070371

    Open questions at the time
    • Direct molecular link between BRAT1 and Akt/Erk activation not identified
    • Single-lab study
  6. 2015 High

    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

    PMID:25631046

    Open questions at the time
    • Ubiquitin chain type and acceptor sites not mapped
    • Link between nuclear BRAT1 and its Integrator function not yet made
  7. 2019 Medium

    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

    PMID:31742228

    Open questions at the time
    • Negative result; does not identify the actual disease-relevant function
    • Single variant in a single lab
  8. 2022 High

    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

    PMID:36028512

    Open questions at the time
    • Does not show how BRAT1 is integrated into Integrator architecture
    • Does not establish the gene-regulatory consequence for neuronal programs
  9. 2024 High

    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

    PMID:37609215 PMID:38805275

    Open questions at the time
    • 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
  10. 2026 High

    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

    PMID:42116163

    Open questions at the time
    • Does not establish how snRNA misprocessing produces the specific neurodegenerative phenotype
    • Genotype-to-processing-defect relationship across all variants not exhaustive

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified structural or regulatory model linking the three activities
  • Unclear which functions are direct versus secondary consequences of BRAT1 loss

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005654 nucleoplasm 1
Pathway
R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1266738 Developmental Biology 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
ATMBRCA1DNA-PKCSINTS11INTS9NDFIP1PP2ASMC1
Complex memberships
BRAT1-INTS9-INTS11 trimeric complexIntegrator complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Yeast two-hybrid, siRNA knockdown, in vitro phosphatase inhibition assay with purified BRAT1, okadaic acid rescue experiment The Journal of biological chemistry High 16452482
2010 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. Co-immunoprecipitation, siRNA knockdown, Western blot for phosphorylation Genes & cancer Medium 21779444
2011 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. Co-immunoprecipitation, domain-mapping pulldown, siRNA knockdown, Western blot for phosphorylation Experimental and therapeutic medicine Medium 22977523
2013 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. X-ray crystallography (2.2 Å), isothermal titration calorimetry Biochemistry High 24073851
2013 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. Conditional gene deletion (MEFs), Western blot for mTOR pathway proteins, cell cycle analysis Journal of cancer biology & research Medium 25657994
2014 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. Stable shRNA knockdown, glycolysis assay, mitochondrial ROS measurement (MitoSOX), PDH activity assay, Western blot, SC79 rescue experiment, in vitro/in vivo tumorigenic assays BMC cancer Medium 25070371
2015 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. siRNA knockdown of Ndfip1, confocal microscopy for subcellular localization, Western blot for ubiquitination and ATM phosphorylation, brain injury model The Journal of biological chemistry High 25631046
2019 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. Western blotting of patient lymphocytes/fibroblasts, ATM kinase activation assay after IR, PDH phosphorylation assay, oxygen consumption rate measurement (Seahorse) Neurology. Genetics Medium 31742228
2022 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. Co-immunoprecipitation, RNA-seq, RT-PCR for snRNA/snoRNA processing, patient-derived cell analysis Nature communications High 36028512
2023 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. Co-immunoprecipitation, ChIP-seq/ChIP, siRNA/shRNA knockdown, neural differentiation assay, rescue with wild-type vs. mutant BRAT1 bioRxivpreprint Medium 37609215
2024 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. Co-immunoprecipitation, ChIP-seq, siRNA/shRNA knockdown, rescue reconstitution with wild-type vs. mutant BRAT1, mouse ESC differentiation assay Proceedings of the National Academy of Sciences of the United States of America High 38805275
2024 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. 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 Cellular and molecular life sciences : CMLS Medium 39833546
2026 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. RT-qPCR, FISH for nuclear U1 snRNA retention in patient-derived cells, Western blot; zebrafish ints11 KO model validation Genome medicine High 42116163

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 BRAT1 deficiency causes increased glucose metabolism and mitochondrial malfunction. BMC cancer 49 25070371
2006 ATM activation by ionizing radiation requires BRCA1-associated BAAT1. The Journal of biological chemistry 49 16452482
2016 BRAT1 mutations present with a spectrum of clinical severity. American journal of medical genetics. Part A 39 27282546
2014 Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly. Journal of human genetics 36 25319849
2015 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. The Journal of biological chemistry 28 25631046
2014 Lethal neonatal rigidity and multifocal seizure syndrome--report of another family with a BRAT1 mutation. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 27 25500575
2016 BRAT1 mutations are associated with infantile epileptic encephalopathy, mitochondrial dysfunction, and survival into childhood. American journal of medical genetics. Part A 26 27282648
2015 BRAT1-related disease--identification of a patient without early lethality. American journal of medical genetics. Part A 25 26494257
2022 BRAT1 links Integrator and defective RNA processing with neurodegeneration. Nature communications 20 36028512
2010 Regulation of ATM/DNA-PKcs Phosphorylation by BRCA1-Associated BAAT1. Genes & cancer 20 21779444
2015 Early-Onset Severe Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of Causes. Neuropediatrics 17 26535877
2018 BRAT1 Mutation: The First Reported Case of Chinese Origin and Review of the Literature. Journal of neuropathology and experimental neurology 16 30346566
2011 Functional interaction of BRCA1/ATM-associated BAAT1 with the DNA-PK catalytic subunit. Experimental and therapeutic medicine 16 22977523
2019 Homozygous pathogenic variant in BRAT1 associated with nonprogressive cerebellar ataxia. Neurology. Genetics 15 31742228
2013 The Potential Role of BRCA1-Associated ATM Activator-1 (BRAT1) in Regulation of mTOR. Journal of cancer biology & research 15 25657994
2017 Lethal neonatal rigidity and multifocal seizure syndrome with a new mutation in BRAT1. Epilepsy & behavior case reports 13 28752061
2013 Structural basis for the BRCA1 BRCT interaction with the proteins ATRIP and BAAT1. Biochemistry 13 24073851
2024 Neuronal differentiation requires BRAT1 complex to remove REST from chromatin. Proceedings of the National Academy of Sciences of the United States of America 12 38805275
2021 Clinical variability at the mild end of BRAT1-related spectrum: Evidence from two families with genotype-phenotype discordance. Human mutation 12 34747546
2020 An intronic variant in BRAT1 creates a cryptic splice site, causing epileptic encephalopathy without prominent rigidity. Acta neurologica Belgica 12 33040300
2018 Clinico-pathological correlation in case of BRAT1 mutation. Folia neuropathologica 11 30786674
2022 Involvement of B-aat1 and Cbs in regulating mantle pigmentation in the Pacific oyster (Crassostrea gigas). Molecular biology reports 9 36335521
2021 Novel variant in BRAT1 with the lethal neonatal rigidity and multifocal seizure syndrome. Pediatric research 9 33790413
2020 A novel pathogenic variant of BRAT1 gene causes rigidity and multifocal seizure syndrome, lethal neonatal. The International journal of neuroscience 8 32345087
2022 Compound heterozygous loss-of-function variants in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome. Molecular genetics & genomic medicine 6 36367347
2017 Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1. Ophthalmic genetics 6 28635423
2023 BRAT1 associates with INTS11/INTS9 heterodimer to regulate key neurodevelopmental genes. bioRxiv : the preprint server for biology 5 37609215
2022 Novel Biallelic Variant in the BRAT1 Gene Caused Nonprogressive Cerebellar Ataxia Syndrome. Frontiers in genetics 5 35360849
2025 BRAT1 - a new therapeutic target for glioblastoma. Cellular and molecular life sciences : CMLS 4 39833546
2022 Serum Anti-BRAT1 is a Common Molecular Biomarker for Gastrointestinal Cancers and Atherosclerosis. Frontiers in oncology 4 35656505
2024 Novel BRAT1 Deep Intronic Variant Affects Splicing Regulatory Elements Causing Cerebellar Hypoplasia Syndrome: Genotypic and Phenotypic Expansion. Clinical genetics 2 39586739
2024 Clinical characteristics of BRAT1-related disease: a systematic literature review. Acta neurologica Belgica 1 38607605
2024 Novel BRAT1 variant associated with neurodevelopmental disorder with cerebellar atrophy and seizure: Case report and a literature review. Epilepsy & behavior reports 1 39188779
2023 BRAT1 Mutation Retrospective Diagnosis: A Case Report. Cureus 1 37009381
2026 BRAT1 gene compound heterozygous mutations causing lethal neonatal rigidity and multifocal seizure syndrome: a case report. Frontiers in pediatrics 0 41737239
2026 Unprocessed U1 snRNAs as a biomarker of INTS11- and BRAT1-related neurodevelopmental disorders. Genome medicine 0 42116163
2024 BRAT1-Associated Leukodystrophy Exacerbated by Classic Hodgkin Lymphoma-Directed Therapy. The neurologist 0 38019165

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