BRAT1 is an ARM/HEAT-repeat assembly factor that binds the Integrator endonuclease INTS11 and its partner INTS9. Its conserved C-terminal motif occupies the INTS11 active site, inhibiting premature RNA cleavage while stabilizing an assembly intermediate. BRAT1 acts predominantly in the cytoplasm and can assist nuclear delivery of the cleavage module; it dissociates as the mature INTS4–INTS9–INTS11 module forms. Earlier studies also implicate BRAT1 in maintaining ATM and DNA-PK-associated damage signaling and in context-dependent cell survival, proliferation and mitochondrial homeostasis. Biallelic pathogenic variants cause a spectrum of neurological disease including neonatal rigidity with multifocal seizures and neurodevelopmental disease with cerebellar atrophy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001934 positive regulation of protein phosphorylation | IMP PMID:22977523 Functional interaction of BRCA1/ATM-associated BAAT1 with th... | KEEP AS NON CORE | Summary: BRAT1 supports damage-induced protein phosphorylation. Reason: BRAT1 depletion reduced NCS-induced phosphorylation of DNA-PKcs Ser2056 and SMC1 Ser966 in human cells. This supports positive regulation of phosphorylation in a DNA-damage context, without assigning kinase catalysis to BRAT1 or to SMC1. The supplemental full Results leave altered kinase activity, phosphatase activity and localization as possible mechanisms. Supporting Evidence: PMID:22977523 phosphorylation was reduced when BAAT1 was depleted by siRNA. |
| GO:0005515 protein binding | IPI PMID:16452482 ATM activation by ionizing radiation requires BRCA1-associat... | KEEP AS NON CORE | Summary: The BRAT1–BRCA1 association is supported. Reason: The original abstract reports isolation of BAAT1 through BRCA1 yeast two-hybrid screening. Retain the specific P38398 partner assertion as non-core under the project curation instruction; this experiment does not establish an adapter, DNA-binding or catalytic activity of BRAT1. Supporting Evidence: PMID:16452482 by yeast two-hybrid screening |
| GO:0005515 protein binding | IPI PMID:16452482 ATM activation by ionizing radiation requires BRCA1-associat... | MODIFY | Summary: Refine the ATM interaction to serine/threonine kinase binding. Reason: The abstract explicitly reports BAAT1 binding to ATM and modulation of its Ser1981 phosphorylation. The source partner Q13315 is ATM, a serine/threonine protein kinase, so the kinase-binding term is more informative than generic protein binding. It does not assign ATM catalysis to BRAT1. Detailed assay conditions remain bounded by the abstract and the subsequent source-specific association study. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22977523 Functional interaction of BRCA1/ATM-associated BAAT1 with th... | MODIFY | Summary: Refine the DNA-PKcs interaction to serine/threonine kinase binding. Reason: The canonical abstract identifies DNA-PKcs binding. Supplemental full Results and Methods show recovery of P78527/DNA-PKcs with human BAAT1 fragments and FLAG-tagged full-length BAAT1 from 293T lysates, with NCS-dependent association changes. This supports kinase binding at the curated IPI association level; the lysate experiments do not prove an isolated purified binary interaction. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22977523 Functional interaction of BRCA1/ATM-associated BAAT1 with th... | MODIFY | Summary: Refine the independently assayed ATM interaction to kinase binding. Reason: The supplemental Results explicitly show ATM recovery with human BAAT1 GST fragments and full-length FLAG-BAAT1 in 293T cells. Preserve Q13315 and the original publication. ATM is the serine/threonine kinase partner; BRAT1 is not assigned catalytic activity. Co-purification from lysate does not establish purified binary binding. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22977523 Functional interaction of BRCA1/ATM-associated BAAT1 with th... | KEEP AS NON CORE | Summary: Retain the SMC1A association without transferring enzyme activity. Reason: The canonical abstract and supplemental Results support SMC1 recovery with BAAT1 GST fragments from human 293T lysate. SMC1A/Q14683 is a cohesin ATPase and phosphorylation substrate, not one of the protein kinases in this experiment. The assay supports association but does not establish that BRAT1 is a cohesin subunit or enzyme activator. Retain the correct generic binding under the project instruction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25631046 Nedd4 family interacting protein 1 (Ndfip1) is required for ... | KEEP AS NON CORE | Summary: Retain NDFIP1-associated trafficking with explicit curator deference. Reason: The abstract establishes NDFIP1-dependent BRAT1 ubiquitination and nuclear trafficking, and the reviewed UniProt record explicitly records the NDFIP1 interaction. The original target-specific binding experiment was not independently inspected: the normal cache is abstract-only and direct PMC access returned a challenge. Retain the established Q9BT67 association by curator deference, without claiming a purified binary interaction or assigning NDFIP1/NEDD4 catalytic functions to BRAT1. |
| GO:0005515 protein binding | IPI PMID:25657994 The Potential Role of BRCA1-Associated ATM Activator-1 (BRAT... | MODIFY | Summary: Refine mTOR association to serine/threonine kinase binding. Reason: The source Results show recovery of mTOR/P42345 with GST-tagged human BRAT1 and selected BRAT1 fragments from 293 cell lysate. This supports the curated kinase-association assertion and its partner-class refinement. It does not establish purified binary binding, BRAT1 kinase activity or obligatory membership in mature mTOR complexes. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25657994 The Potential Role of BRCA1-Associated ATM Activator-1 (BRAT... | KEEP AS NON CORE | Summary: Retain the Raptor association as non-core. Reason: Raptor/Q8N122 was recovered with GST-tagged human BRAT1 constructs from 293 cell lysate. The assay establishes association under those conditions, not purified binary binding or BRAT1 membership in every mTORC1 complex. No distinct BRAT1 adapter activity is established by this pull-down alone; retain the correct generic binding under the project instruction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The A6NI15/MSGN1 screen edge requires target-specific evidence. Reason: The cached HuRI article explains the binary interaction screen but the specific BRAT1–A6NI15/MSGN1 experiment or supplemental edge was not inspected. Preserve the exact original partner identifier and publication; neither general screen quality nor another BRAT1 interaction independently verifies this edge. Uncertainty concerns this source assertion, not the usefulness of generic protein binding. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The Q13287/NMI screen edge requires target-specific evidence. Reason: The cached HuRI article explains the binary interaction screen but the specific BRAT1–Q13287/NMI experiment or supplemental edge was not inspected. Preserve the exact original partner identifier and publication; neither general screen quality nor another BRAT1 interaction independently verifies this edge. Uncertainty concerns this source assertion, not the usefulness of generic protein binding. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The Q8N6Y0/USHBP1 screen edge requires target-specific evidence. Reason: The cached HuRI article explains the binary interaction screen but the specific BRAT1–Q8N6Y0/USHBP1 experiment or supplemental edge was not inspected. Preserve the exact original partner identifier and publication; neither general screen quality nor another BRAT1 interaction independently verifies this edge. Uncertainty concerns this source assertion, not the usefulness of generic protein binding. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The Q9H0I2/ENKD1 screen edge requires target-specific evidence. Reason: The cached HuRI article explains the binary interaction screen but the specific BRAT1–Q9H0I2/ENKD1 experiment or supplemental edge was not inspected. Preserve the exact original partner identifier and publication; neither general screen quality nor another BRAT1 interaction independently verifies this edge. Uncertainty concerns this source assertion, not the usefulness of generic protein binding. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The KLF11 screen interaction remains unadjudicated. Reason: The abstract describes a large neurodegeneration interactome but does not expose the BRAT1–O14901/KLF11 target experiment. The screen table and original construct conditions were not inspected. Preserve the curated assertion without treating its absence from the abstract as a wrong-gene error. Supporting Evidence: |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization is compatible with BRAT1 function. Reason: The inherited localization is corroborated by human experimental nuclear-localization annotations and the assembly/import study. Predominantly cytoplasmic localization in other conditions is not exclusive localization. The PAINT tree and ancestral node were not independently audited; the target appearing in WITH/FROM is legitimate experimental grounding, not circularity. |
| GO:0005634 nucleus | IDA PMID:16452482 ATM activation by ionizing radiation requires BRCA1-associat... | ACCEPT | Summary: BRAT1 can localize at nuclear DNA-damage sites. Reason: The original abstract explicitly reports BAAT1 localization to DNA double-strand breaks in the ionizing-radiation response. This supports the broad nuclear term while leaving detailed spatial imaging to the original curator. It does not imply constitutive or exclusive nuclear residence. Supporting Evidence: |
| GO:0005634 nucleus | IDA PMID:25631046 Nedd4 family interacting protein 1 (Ndfip1) is required for ... | ACCEPT | Summary: NDFIP1-dependent BRAT1 nuclear trafficking is supported. Reason: The abstract reports nuclear translocation of BRAT1 following NDFIP1-mediated ubiquitination and genotoxic stress. Retain the observed localization without assigning nuclear residence to every cell state or all three products. Supporting Evidence: PMID:25631046 BRAT1 failed to translocate |
| GO:0005634 nucleus | IDA PMID:39032489 Assembly mechanism of Integrator's RNA cleavage module. | ACCEPT | Summary: Nuclear BRAT1 is consistent with cleavage-module maturation. Reason: The assembly study identifies BRAT1-assisted nuclear delivery of INTS9–INTS11 and BRAT1 release during maturation. Retain the original localization assay with curator deference; the accessible abstract is not a complete imaging audit. This transient assembly factor is not assigned stable membership in mature Integrator. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic nuclear localization is experimentally corroborated. Reason: Human nuclear-translocation and assembly studies support this broad localization independently of the electronic transfer. Preserve the original mouse/localization-rule source fields and avoid inferring exclusive localization or a product-specific effect. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Retain the curated nucleoplasmic localization with assay limits. Reason: The HPA immunofluorescence annotation is compatible with experimentally supported nuclear trafficking. Its specific antibody image and cell-line context were not independently inspected. Retain the credible compartment assertion by curator deference, without inventing subnuclear localization details. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:25631046 Nedd4 family interacting protein 1 (Ndfip1) is required for ... | ACCEPT | Summary: BRAT1 has a cytoplasmic pool before nuclear trafficking. Reason: The NDFIP1 study describes regulated nuclear entry of BRAT1. This cytoplasmic assignment is independently corroborated by the human fractionation and immunofluorescence results of the Integrator study; cytoplasmic and nuclear annotations describe compatible states. |
| GO:0005737 cytoplasm | IDA PMID:39032489 Assembly mechanism of Integrator's RNA cleavage module. | ACCEPT | Summary: Cytoplasmic BRAT1 participates in Integrator-module biogenesis. Reason: The assembly mechanism places BRAT1 with INTS9–INTS11 before nuclear entry. The localization is independently consistent with the companion human fractionation study. Preserve the source assay and do not broaden cytoplasmic localization into mitochondrial localization. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic cytoplasmic localization is directly corroborated. Reason: Human fractionation and immunofluorescence identify a predominant cytoplasmic BRAT1 pool. Preserve the electronic source fields; the inference agrees with experimental evidence and does not exclude regulated nuclear trafficking. Supporting Evidence: |
| GO:0005829 cytosol | IDA PMID:39032490 Cytoplasmic binding partners of the Integrator endonuclease ... | ACCEPT | Summary: The human cytosolic BRAT1 pool is supported. Reason: The canonical abstract places BRAT1-associated stabilization of INTS11 in the cytoplasm. Supplemental human HEK293T fractionation and HCT116 immunofluorescence support the source cytosolic localization, with matched knockout controls. No exclusive localization claim is made. Supporting Evidence: |
| GO:0006006 glucose metabolic process | IMP PMID:25070371 BRAT1 deficiency causes increased glucose metabolism and mit... | MARK AS OVER ANNOTATED | Summary: Metabolic perturbation does not establish a glucose-metabolism step. Reason: The full source shows increased glucose consumption and lactate accumulation after BRAT1 knockdown alongside mitochondrial dysfunction. GO:0006006 describes chemical reactions and pathways involving glucose; the experiments do not identify a glucose-metabolic reaction, transport step or specific metabolic regulatory mechanism performed by BRAT1. Preserve the phenotype as secondary biology, without treating BRAT1 as a metabolic enzyme or inferring that the observed compensatory response is a direct pathway role. Supporting Evidence: |
| GO:0006915 apoptotic process | IMP PMID:25070371 BRAT1 deficiency causes increased glucose metabolism and mit... | MODIFY | Summary: Refine the survival phenotype to negative regulation of apoptosis. Reason: BRAT1 silencing increased constitutive apoptosis and sensitivity to glucose deprivation in the examined human cancer cells. This supports an anti-apoptotic influence in that context rather than BRAT1 executing the apoptotic program. The broad negative-regulation term does not require BRAT1 to be a caspase or establish a particular mitochondrial apoptosis pathway; this remains a non-core perturbation phenotype. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:25070371 silencing of BRAT1 increased constitutive apoptosis |
| GO:0006974 DNA damage response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited DNA-damage response remains supported. Reason: Human ATM/DNA-PK signaling experiments corroborate this broad response despite the newer Integrator assembly mechanism. No target-specific loss or phylogenetic conflict is established. The PAINT node/tree was not inspected and donor number or self-support is not used as a criticism. |
| GO:0006974 DNA damage response | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Retain the family-based DNA-damage response inference. Reason: The InterPro-based inference agrees with independent BRAT1 perturbation and association experiments in damage signaling. The direct molecular link between this response and Integrator biogenesis remains unresolved; the newer mechanism does not invalidate the older experimental context. |
| GO:0006974 DNA damage response | IMP PMID:25631046 Nedd4 family interacting protein 1 (Ndfip1) is required for ... | KEEP AS NON CORE | Summary: Regulated BRAT1 trafficking contributes to a damage-response context. Reason: The source abstract reports genotoxic-stress-associated NDFIP1 induction, BRAT1 ubiquitination and nuclear translocation, and ATM phosphorylation. Retain the curated IMP response with the limitation that complete original assays were not inspected. BRAT1 is not assigned DNA repair catalysis or ubiquitin ligase activity. Supporting Evidence: |
| GO:0008283 cell population proliferation | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Proliferation effects are supported but depend on cell context. Reason: BRAT1 knockdown reduced expansion of several human cancer-cell populations, supporting a non-core proliferation relationship independently of the InterPro mapping. The companion Integrator study found no overt growth defect in BRAT1-null HCT116 or human embryonic stem cells, so the effect is not a universal requirement for proliferation. |
| GO:0008283 cell population proliferation | IMP PMID:25070371 BRAT1 deficiency causes increased glucose metabolism and mit... | KEEP AS NON CORE | Summary: Retain the measured cancer-cell population proliferation phenotype. Reason: Cell counts, cell-cycle measurements and human-cell xenografts in the source show reduced population expansion after BRAT1 depletion. These are context-dependent phenotypes rather than an intrinsic mitogenic activity. The absence of an overt growth defect in the later HCT116/hESC knockout models limits universality but does not refute these experiments. |
| GO:0008428 ribonuclease inhibitor activity | IDA PMID:39032489 Assembly mechanism of Integrator's RNA cleavage module. | MODIFY | Summary: Specify inhibition of the INTS11 endoribonuclease. Reason: BRAT1 directly blocks the active site of INTS11 during cleavage-module maturation. INTS11 is an endoribonuclease, so GO:0060698 is the supported child of the broad ribonuclease-inhibitor term. This is BRAT1 inhibition activity, not RNA cleavage by BRAT1. No redundant NEW annotation is needed. Proposed replacements: endoribonuclease inhibitor activity Supporting Evidence: PMID:39032489 maintain INTS9-11 inactive during maturation |
| GO:0008428 ribonuclease inhibitor activity | IDA PMID:39032490 Cytoplasmic binding partners of the Integrator endonuclease ... | MODIFY | Summary: Specify the structurally supported endoribonuclease inhibition. Reason: The human INTS9–INTS11–BRAT1 structure places the BRAT1 C-terminal motif in the INTS11 active site. The supplemental main Results and Discussion explain substrate occlusion and show that DCY-motif mutants fail full functional rescue. Refine the inhibitor target to endoribonuclease; do not assign BRAT1 endonuclease catalysis or extrapolate the distinct UBE3D–CPSF73 interaction to BRAT1. Proposed replacements: endoribonuclease inhibitor activity Supporting Evidence: PMID:39032490 BRAT1/CG7044 is captured in the active site of INTS11 |
| GO:0010212 response to ionizing radiation | IMP PMID:16452482 ATM activation by ionizing radiation requires BRCA1-associat... | KEEP AS NON CORE | Summary: BRAT1 participates in the response to ionizing radiation. Reason: The original abstract directly links BAAT1 depletion to reduced ATM/CHK2 phosphorylation following ionizing radiation and also reports purified BAAT1 partially protecting ATM from PP2A-mediated dephosphorylation. Substrate protection does not establish a general phosphatase inhibitor activity. Retain this damage-response context as non-core, without replacing it with a more specific repair pathway or claiming kinase activity for BRAT1. Supporting Evidence: |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: Recovered in a membrane-fraction proteome without protein-specific evidence that it associates with membranes. Reason: UniProt: nucleus and cytoplasm (ECO:0000269); no membrane association on record. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: UNDECIDED.) Supporting Evidence: |
| GO:0016477 cell migration | IMP PMID:25070371 BRAT1 deficiency causes increased glucose metabolism and mit... | KEEP AS NON CORE | Summary: Retain the measured migration effect with its experimental controls. Reason: The source includes a wound assay after mitomycin-C pretreatment to suppress proliferation and a separate migration-chamber assay. The decreased movement after BRAT1 depletion is therefore not supported solely by reduced cell counts. Retain the contextual migration phenotype without assigning BRAT1 motor or cytoskeletal activity. Supporting Evidence: |
| GO:0030307 positive regulation of cell growth | IMP PMID:25070371 BRAT1 deficiency causes increased glucose metabolism and mit... | MARK AS OVER ANNOTATED | Summary: Population expansion does not demonstrate individual-cell growth. Reason: GO cell growth concerns an increase in individual-cell size and biosynthetic mass. The cited source assesses cell numbers, cell-cycle distributions and xenograft expansion, but does not establish increased individual-cell size or biomass driven by BRAT1. The supported population-proliferation phenotype is already retained separately; do not manufacture a redundant replacement row from the same measurements. Supporting Evidence: |
| GO:0034504 protein localization to nucleus | IDA PMID:39032489 Assembly mechanism of Integrator's RNA cleavage module. | ACCEPT | Summary: BRAT1 can facilitate nuclear delivery of the cleavage module. Reason: The source explicitly reports BRAT1-assisted import of INTS9–INTS11. Retain that assembly-pathway function without claiming BRAT1 is an importin or absolutely required for every import event. In the companion study, residual INTS11 remained nuclear after BRAT1 knockout in HCT116 cells; assistance and stabilization need not imply obligatory transport. Supporting Evidence: PMID:39032489 BRAT1 facilitates import of INTS9-11 into the nucleus |
| GO:0051646 mitochondrion localization | IMP PMID:25070371 BRAT1 deficiency causes increased glucose metabolism and mit... | MARK AS OVER ANNOTATED | Summary: Altered mitochondrial distribution does not establish BRAT1 participation in positioning mitochondria. Reason: The source reports more condensed mitochondria after BRAT1 depletion in HeLa cells, using a mitochondrial-dye morphology assay described in the main Results and Figure S2 caption. GO:0051646 concerns establishing or maintaining mitochondrial position. The reported phenotype supports an effect on organelle distribution, but does not identify a positioning step performed by BRAT1 or distinguish it from the broader mitochondrial dysfunction in the same cells. Mark the process assertion as over-annotated while preserving the reported phenotype; this is not a claim that the experimental observation is wrong or that BRAT1 localizes to mitochondria. The supplemental image itself was not inspected. Supporting Evidence: |
| GO:0160234 integrator complex assembly | IDA PMID:39032489 Assembly mechanism of Integrator's RNA cleavage module. | ACCEPT | Summary: BRAT1 directly assists Integrator cleavage-module assembly. Reason: The source identifies BRAT1 and WDR73 as biogenesis factors maintaining an inactive INTS9–INTS11 intermediate, followed by nuclear delivery, INTS4 association and IP6-dependent BRAT1 release. Assembly-factor participation does not require BRAT1 to remain in mature Integrator. Supporting Evidence: |
| GO:0160234 integrator complex assembly | IDA PMID:39032490 Cytoplasmic binding partners of the Integrator endonuclease ... | ACCEPT | Summary: The INTS9–INTS11 assembly intermediate is directly supported. Reason: The human ternary structure, INTS9/INTS11 destabilization after BRAT1 loss, and wild-type-versus-DCY-mutant rescue support cleavage-module biogenesis. BRAT1-bound INTS9/INTS11 is structurally distinct from the mature INTS4-containing module, so this annotation does not imply stable membership or transcriptional cleavage catalysis by BRAT1. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which of the older ATM/DNA-PK, survival and metabolic effects depend on Integrator biogenesis, and which reflect separable BRAT1 interactions?
Q: How do the three named BRAT1 products differ in stability, binding and assembly activity? Existing unqualified GOA assertions do not establish equivalent activity of all three products.
Q: Can the original partner-specific HuRI/KLF11 records and the YTS membrane-proteome detection be inspected to resolve the remaining source assertions?
Q: Is there an appropriate cellular-component term for the transient BRAT1–WDR73–INTS9–INTS11 assembly intermediate? Its composition and maturation role should be distinguished from mature Integrator before asserting complex membership.
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