BRIP1 (Fanconi anemia group J protein, FANCJ; formerly BACH1/BRCA1-associated C-terminal helicase 1) is an ATP-dependent 5'-to-3' DNA helicase of the Rad3/XPD (DinG) superfamily 2 subfamily. It is a DNA-dependent ATPase that couples ATP hydrolysis to translocation along ssDNA and unwinding of duplex DNA, and it requires a [4Fe-4S] iron-sulfur cluster for helicase activity. The enzyme preferentially engages forked duplex substrates with a 5' single-stranded tail and can resolve non-B DNA structures, most notably G-quadruplexes, thereby removing replication-fork roadblocks and safeguarding genome stability. BRIP1 functions in homologous recombination repair of DNA double-strand breaks in concert with BRCA1, to whose C-terminal BRCT domains it binds in a phosphorylation-dependent manner (via phospho-Ser990), and it acts late in the Fanconi anemia interstrand crosslink (ICL) repair pathway, after FANCD2 ubiquitination, where its direct interaction with the mismatch-repair MutLalpha component MLH1 is required to correct the crosslink response. At stalled or damaged replication forks it collaborates with RPA and BLM and promotes repair of DNA-protein crosslinks by using its ATPase to unfold the protein adduct, exposing the underlying DNA for cleavage by the SPRTN protease. BRIP1 localizes chiefly to the nucleoplasm and forms DNA-damage-inducible nuclear foci; its Fe-S cluster is matured by the cytosolic iron-sulfur assembly (CIA) machinery (CIAO1, CIAO2B, MMS19), consistent with a minor cytoplasmic pool. Biallelic loss-of-function causes Fanconi anemia complementation group J, and monoallelic pathogenic variants confer susceptibility to breast and ovarian cancer.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003678 DNA helicase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that BRIP1 enables DNA helicase activity, from the Rad3/XPD helicase family tree. This is correct but generic; BRIP1 is specifically a 5'-3' DNA helicase (GO:0043139), annotated separately with experimental support. Reason: BRIP1 is a bona fide ATP-dependent DNA helicase, directly demonstrated biochemically. The parent term "DNA helicase activity" is accurate at a general level; the more specific 5'-3' directionality is captured by GO:0043139 elsewhere in the annotation set. Supporting Evidence: PMID:14983014 we show that BACH1 is both a DNA-dependent ATPase and a 5′-to-3′ DNA helicase |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that BRIP1 is active in the nucleus. Consistent with its role as a nuclear DNA repair/replication helicase. Reason: BRIP1 acts on nuclear DNA in HR, ICL and DPC repair, and forms nuclear DNA-damage foci. Nuclear localization is well supported experimentally. Supporting Evidence: PMID:17596542 dependent on the presence of BRCA1, FANCJ colocalizes with RPA in nuclear foci after DNA damage |
| GO:0006289 nucleotide-excision repair | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA inference of involvement in nucleotide-excision repair, propagated from the Rad3/XPD family (which includes the NER helicase XPD). There is no FANCJ-specific evidence that BRIP1 participates in classical NER. Reason: BRIP1/FANCJ's characterized biological roles are interstrand-crosslink repair, homologous recombination, DNA-protein-crosslink repair, and G-quadruplex resolution — not the classical NER pathway performed by its paralog XPD. The term appears to be over-propagated across the helicase family tree rather than reflecting a demonstrated FANCJ function. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:P18074 XPD (ERCC2) is the Rad3/XPD-family paralog that performs nucleotide-excision repair; FANCJ diverged to ICL/HR/DPC/G4 functions and is not a NER factor. |
| GO:1990918 double-strand break repair involved in meiotic recombination | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA inference (from mouse/worm homologs) of a role in meiotic recombination-associated DSB repair. BRIP1 is highly expressed in testis, making a meiotic role plausible, but this is not an established core somatic function in human. Supported at the ortholog level: Fancj (GT/GT) mice show altered processing of meiotic crossover sites during prophase I (increased MLH1 focus frequency and chiasmata), consistent with a role in the DSB-repair events of meiotic recombination. Reason: Plausible for the family and consistent with testis-enriched expression, but the human gene's characterized, disease-relevant functions are somatic genome-maintenance activities (ICL/HR/DPC repair). Retained as a non-core, context-specific process. Supporting Evidence: PMID:26490168 indicative of increased DSB repair via CO PMID:26490168 MLH1 focus frequency is increased in Fancj (GT/GT) males |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro-based electronic annotation of generic nucleic acid binding. True but uninformative; BRIP1 binds DNA specifically. Reason: "Nucleic acid binding" is a high-level parent that adds little; the specific and informative activity is DNA binding / DNA helicase activity, which are separately annotated. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based inference of DNA binding. Correct and relevant — BRIP1 binds and translocates on DNA as part of its helicase mechanism. Reason: DNA binding is experimentally supported (substrate binding/unwinding assays) and is a genuine molecular capability of the enzyme. Supporting Evidence: PMID:15878853 BACH1 preferentially binds and unwinds a forked duplex substrate |
| GO:0003678 DNA helicase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based inference of DNA helicase activity. Correct but generic relative to the experimentally established 5'-3' directionality. Reason: Consistent with the experimentally demonstrated helicase activity of BRIP1. Supporting Evidence: PMID:14983014 we show that BACH1 is both a DNA-dependent ATPase and a 5′-to-3′ DNA helicase |
| GO:0004386 helicase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based inference of generic helicase activity, a parent of DNA helicase activity. Reason: Correct high-level term; the more specific DNA/5'-3' helicase terms are annotated separately with experimental support. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based inference of ATP binding. Supported by the Walker A/ATP-binding motif and by the DNA-dependent ATPase activity of the protein. Reason: BRIP1 contains a helicase ATP-binding domain (residues 11-442, ATP-binding site 185-192) and hydrolyzes ATP; ATP binding is a prerequisite for its motor activity. Supporting Evidence: PMID:14983014 ATP binding and hydrolysis are prerequisites for the strand separation activity of all known helicases |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location keyword mapping to nucleus. Correct. Reason: Nuclear localization of BRIP1 is well established experimentally. Supporting Evidence: PMID:17596542 FANCJ colocalizes with RPA in nuclear foci after DNA damage |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location keyword mapping to cytoplasm. BRIP1 has a minor cytoplasmic pool, consistent with maturation of its Fe-S cluster by the cytosolic iron-sulfur assembly (CIA) machinery. Reason: A cytoplasmic pool is documented (interaction with CIAO1/CIAO2B/MMS19), but BRIP1's functional site of action is nuclear; cytoplasmic localization is a non-core, cofactor-maturation-related compartment. Supporting Evidence: PMID:23585563 IOP1 functions in the MMS19-dependent CIA pathway |
| GO:0006281 DNA repair | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning electronic annotation of involvement in DNA repair. Correct at a general level. Reason: BRIP1 is a core genome-maintenance/DNA-repair factor; the general term is accurate, with more specific processes (HR, ICL, DPC repair) annotated elsewhere. Supporting Evidence: PMID:11301010 contributes to its DNA repair function |
| GO:0016818 hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro-based inference of a high-level phosphoanhydride hydrolase activity, a distant parent of ATP hydrolysis activity. Reason: Overly general; the informative and experimentally supported activity is ATP hydrolysis activity (GO:0016887), annotated separately. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000116 | ACCEPT | Summary: RHEA/Rhea-mapping electronic annotation of ATP hydrolysis activity. Correct and experimentally corroborated (DNA-dependent ATPase). Reason: BRIP1 is a DNA-dependent ATPase; ATP hydrolysis fuels its translocase/helicase activity. Supporting Evidence: PMID:14983014 These results indicate that BACH1 possesses an intrinsic, DNA-dependent ATPase activity |
| GO:0043139 5'-3' DNA helicase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC 5.6.2.3 mapping to 5'-3' DNA helicase activity. This is BRIP1's core molecular function and is strongly supported experimentally. Reason: Directly demonstrated: BRIP1 translocates 5'-to-3' and unwinds duplex DNA in an ATP-dependent manner. Supporting Evidence: PMID:14983014 indicating translocation in the 5′-to-3′ direction with respect to the strand to which the enzyme is bound |
| GO:0005515 protein binding | IPI PMID:15125843 Structure of the BRCT repeats of BRCA1 bound to a BACH1 phos... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation capturing the direct BRIP1-BRCA1 interaction (structure of BRCA1 BRCT repeats bound to a BACH1 phosphopeptide; partner BRCA1/P38398). Reason: Per curation guidance, the generic "protein binding" term is uninformative. The biologically meaningful BRCA1 interaction (via phospho-Ser990 to the BRCA1 BRCT domains) is captured in core_functions and in the DSB/HR process annotations. Supporting Evidence: PMID:11301010 BACH1 binds directly to the BRCT repeats of BRCA1 |
| GO:0005515 protein binding | IPI PMID:15133502 Structure and mechanism of BRCA1 BRCT domain recognition of ... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation for the BRIP1-BRCA1 BRCT interaction (partner BRCA1/P38398; structural/mechanistic study of BRCT recognition of phosphorylated BACH1). Reason: Uninformative generic MF term; the meaningful BRCA1 phospho-peptide interaction is represented in core_functions. |
| GO:0005515 protein binding | IPI PMID:17525340 Abraxas and RAP80 form a BRCA1 protein complex required for ... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (partner BRCA1/P38398) from a study of the Abraxas/RAP80-BRCA1 damage-response complex. Reason: Generic protein-binding term; BRCA1 association is captured more informatively elsewhere. |
| GO:0005515 protein binding | IPI PMID:17581638 The FANCJ/MutLalpha interaction is required for correction o... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotations (partners BRCA1/P38398 and MLH1/P40692). This paper establishes the functionally critical FANCJ-MLH1 (MutLalpha) interaction required for the ICL response. Reason: The generic MF term is uninformative, but the underlying MLH1 interaction is biologically central and is represented in the interstrand-crosslink-repair process annotation and core_functions. Supporting Evidence: PMID:17581638 FANCJ directly interacts with MLH1 independent of BRCA1, through its helicase domain |
| GO:0005515 protein binding | IPI PMID:18285836 Pathogenicity of the BRCA1 missense variant M1775K is determ... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (partner BRCA1/P38398) from a study of the pathogenic BRCA1 M1775K BRCT variant that disrupts phosphopeptide binding. Reason: Generic protein-binding term; BRCA1 interaction is captured elsewhere. |
| GO:0005515 protein binding | IPI PMID:19369211 PALB2 is an integral component of the BRCA complex required ... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (partner BRCA1/P38398) from a study of PALB2 in the BRCA complex for HR repair. Reason: Uninformative MF term; BRCA1/HR-complex association is represented in the HR and DSB-repair process annotations. |
| GO:0005515 protein binding | IPI PMID:21240188 Interaction between the helicases genetically linked to Fanc... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotations (partners BRCA1/P38398 and BLM/P54132). This paper establishes the physical and functional FANCJ-BLM interaction at replication-stress foci. Reason: Generic MF term; the meaningful BLM interaction (co-localization and synergistic unwinding under replication stress) is captured in the notes and informs the genome-maintenance core function. Supporting Evidence: PMID:21240188 FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress |
| GO:0005515 protein binding | IPI PMID:22792074 FANCJ/BACH1 acetylation at lysine 1249 regulates the DNA dam... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotations (partners BRCA1/P38398 and MLH1/P40692) from a study of FANCJ acetylation at Lys-1249 regulating the DNA damage response. Reason: Generic MF term; BRCA1 and MLH1 interactions are represented more informatively elsewhere. |
| GO:0005515 protein binding | IPI PMID:23585563 IOP1 protein is an external component of the human cytosolic... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotations (partners MLH1/P40692 and MMS19/Q96T76). BRIP1 interacts with the CIA machinery component MMS19 (and CIAO1/CIAO2B), relevant to maturation of its Fe-S cluster. Reason: Generic MF term; the CIA/MMS19 interaction (Fe-S cluster maturation) is a documented, biologically meaningful association noted in the review, but the bare "protein binding" term itself is uninformative. Supporting Evidence: PMID:23585563 MMS19 interacts with target proteins |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (partner MLH1/P40692) from a high-throughput variant-cloning/interaction pipeline. Reason: Generic, high-throughput protein-binding annotation; uninformative as a molecular function term. |
| GO:0005515 protein binding | IPI PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (partner BRCA1/P38398) from a DNA-repair network analysis (Shieldin/NHEJ). Reason: Generic protein-binding term; not informative as an MF. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (partner HSD17B14/Q9BPX1) from a systematic binary interactome (HuRI). Not an established functional partner. Reason: High-throughput binary interaction with no established biological relevance to BRIP1 function; the generic MF term is uninformative. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotations (partners MLH1/P40692 and HSD17B14/Q9BPX1) from a proteome-scale interactome (BioPlex). Reason: High-throughput protein-binding data; uninformative as a molecular function term. |
| GO:0005515 protein binding | IPI PMID:34591612 A protein interaction landscape of breast cancer. | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotations (partners BRCA1/P38398 and MLH1/P40692) from a breast-cancer protein interaction landscape. Reason: Generic protein-binding term; the BRCA1 and MLH1 interactions are represented more informatively elsewhere. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (partner MLH1/P40692) from a multimodal cell-map functional-genomics study. Reason: Generic protein-binding term; uninformative as an MF. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) localization to the nucleoplasm. Consistent with BRIP1 acting on nuclear DNA and forming nucleoplasmic damage foci. Reason: Nucleoplasmic localization is the primary functional compartment for a soluble nuclear DNA repair helicase and is corroborated by nuclear-foci data. Supporting Evidence: PMID:17596542 FANCJ colocalizes with RPA in nuclear foci after DNA damage |
| GO:0031965 nuclear membrane | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: Single immunofluorescence (HPA) localization to the nuclear membrane. There is no functional evidence for a nuclear-envelope role for this soluble nucleoplasmic helicase. Reason: Nuclear-membrane signal is not corroborated by any functional study and is likely a peripheral/antibody staining pattern rather than a genuine site of BRIP1 action; retained but flagged as an over-annotation. |
| GO:0005634 nucleus | EXP PMID:17596542 FANCJ (BACH1) helicase forms DNA damage inducible foci with ... | ACCEPT | Summary: Experimental nuclear localization; FANCJ forms DNA-damage-inducible nuclear foci with RPA. Reason: Directly demonstrated nuclear localization and damage-induced focus formation. Supporting Evidence: PMID:17596542 dependent on the presence of BRCA1, FANCJ colocalizes with RPA in nuclear foci after DNA damage |
| GO:0016887 ATP hydrolysis activity | EXP PMID:14983014 The BRCA1-associated protein BACH1 is a DNA helicase targete... | ACCEPT | Summary: Experimental demonstration of intrinsic DNA-dependent ATP hydrolysis by purified BRIP1. Reason: Purified recombinant BRIP1 hydrolyzes ATP in a DNA-stimulated manner; the catalytic-dead K52R mutant lacks this activity. Supporting Evidence: PMID:14983014 These results indicate that BACH1 possesses an intrinsic, DNA-dependent ATPase activity |
| GO:0016887 ATP hydrolysis activity | EXP PMID:20639400 Fanconi anemia group J mutation abolishes its DNA repair fun... | ACCEPT | Summary: Experimental ATP hydrolysis activity; the FANCJ-A349P Fe-S-domain mutant uncouples ATP hydrolysis from productive unwinding. Reason: Corroborates BRIP1 ATPase activity and its dependence on an intact Fe-S domain for coupling to DNA unwinding. Supporting Evidence: PMID:20639400 defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates |
| GO:0016887 ATP hydrolysis activity | EXP PMID:36608669 The FANCJ helicase unfolds DNA-protein crosslinks to promote... | ACCEPT | Summary: Experimental ATPase activity used by FANCJ to unfold DNA-protein crosslinks at replication forks. Reason: FANCJ uses its ATPase activity to unfold protein adducts, directly linking ATP hydrolysis to its DPC-repair function. Supporting Evidence: PMID:36608669 uses its ATPase activity to unfold the protein adduct |
| GO:0043139 5'-3' DNA helicase activity | EXP PMID:20639400 Fanconi anemia group J mutation abolishes its DNA repair fun... | ACCEPT | Summary: Experimental 5'-3' helicase activity; unwinding of forked duplex and G-quadruplex substrates requires coupling of ATP hydrolysis to translocation. Reason: Core molecular function; the Fe-S-domain A349P mutation abolishes coupled unwinding, underscoring that this is the disease-relevant activity. Supporting Evidence: PMID:20639400 The ability of FANCJ to use the energy from ATP hydrolysis to produce the force required to unwind DNA |
| GO:0160225 G-quadruplex unwinding activity | IDA PMID:18426915 FANCJ helicase defective in Fanconia anemia and breast cance... | ACCEPT | Summary: Direct demonstration that FANCJ unwinds G-quadruplex (G4) DNA in an ATPase-dependent manner; RPA stimulates and MSH2/MSH6 inhibits this activity. Reason: A well-established, specific molecular function of BRIP1 that underlies its role in resolving G4 replication-fork roadblocks and maintaining genome stability. Supporting Evidence: PMID:18426915 FANCJ unwound G4 DNA substrates in an ATPase-dependent manner |
| GO:0005634 nucleus | NAS PMID:22369660 BRCA1 tumor suppressor network: focusing on its tail. | ACCEPT | Summary: Author-stated nuclear localization (ComplexPortal-assigned) within the BRCA1 tumor-suppressor network review. Reason: Consistent with abundant experimental evidence for nuclear localization. Supporting Evidence: PMID:17596542 FANCJ colocalizes with RPA in nuclear foci after DNA damage |
| GO:0006281 DNA repair | NAS PMID:22369660 BRCA1 tumor suppressor network: focusing on its tail. | ACCEPT | Summary: Author-stated involvement in DNA repair, from the BRCA1 network review. Correct at a general level. Reason: BRIP1 is a core DNA repair factor; general term accurate, with specific processes annotated separately. Supporting Evidence: PMID:22369660 BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP |
| GO:0035825 homologous recombination | NAS PMID:22369660 BRCA1 tumor suppressor network: focusing on its tail. | ACCEPT | Summary: Author-stated involvement in homologous recombination, consistent with BRIP1's BRCA1-dependent role in HR repair of double-strand breaks. Reason: BRIP1 functions with BRCA1 in homologous recombination repair; supported by loss-of-function HR defects. Supporting Evidence: PMID:11301010 interfered with normal double-strand break repair in a manner that was dependent on its BRCA1 binding function |
| GO:0070532 BRCA1-B complex | IPI PMID:16391231 Multifactorial contributions to an acute DNA damage response... | ACCEPT | Summary: BRIP1 is a component of the BRCA1-B (BRCA1-BACH1) complex (ComplexPortal CPX-4426), one of the mutually exclusive BRCA1 BRCT-phosphopeptide complexes. Reason: BRIP1/BACH1 defines the "B" complex of BRCA1 via its phospho-Ser990/BRCT interaction; membership is well established. Supporting Evidence: PMID:22369660 BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP |
| GO:0005657 replication fork | IDA PMID:36608669 The FANCJ helicase unfolds DNA-protein crosslinks to promote... | ACCEPT | Summary: FANCJ acts at the replication fork, where it binds ssDNA downstream of a DNA-protein crosslink and unfolds the adduct to enable repair. Reason: Directly localized and functionally characterized at replication forks in DPC repair and G4 fork-roadblock resolution. Supporting Evidence: PMID:36608669 FANCJ binds ssDNA downstream of the DPC and uses its ATPase activity to unfold the protein adduct |
| GO:0043139 5'-3' DNA helicase activity | IDA PMID:36608669 The FANCJ helicase unfolds DNA-protein crosslinks to promote... | ACCEPT | Summary: Direct assay of FANCJ 5'-3' helicase activity in the context of DNA-protein crosslink unfolding. Reason: Reinforces the core 5'-3' helicase molecular function. Supporting Evidence: PMID:36608669 we identify a role for the 5'-to-3' helicase FANCJ in DPC repair |
| GO:0106300 protein-DNA covalent cross-linking repair | IDA PMID:36608669 The FANCJ helicase unfolds DNA-protein crosslinks to promote... | ACCEPT | Summary: FANCJ promotes repair of DNA-protein crosslinks (DPCs): it supports CMG bypass and is essential for SPRTN protease activation by unfolding the protein adduct. Reason: A directly demonstrated biological process; FANCJ helicase-mediated protein unfolding enables cleavage of the DPC by SPRTN and translesion synthesis past non-degradable DPCs. Supporting Evidence: PMID:36608669 helicase-mediated protein unfolding enables multiple events in DPC repair |
| GO:0043139 5'-3' DNA helicase activity | IDA PMID:14983014 The BRCA1-associated protein BACH1 is a DNA helicase targete... | ACCEPT | Summary: Direct demonstration of 5'-3' DNA helicase activity of purified BRIP1. Reason: The foundational biochemical characterization establishing BRIP1 as a 5'-3' DNA helicase. Supporting Evidence: PMID:14983014 the BACH1 helicase operates as a 5′-to-3′ unwinding protein |
| GO:0005634 nucleus | IDA PMID:23585563 IOP1 protein is an external component of the human cytosolic... | ACCEPT | Summary: Experimental nuclear localization observed in the study of the CIA (cytosolic iron-sulfur assembly) machinery interactions. Reason: Consistent with predominant nuclear localization of BRIP1. Supporting Evidence: PMID:17596542 FANCJ colocalizes with RPA in nuclear foci after DNA damage |
| GO:0005737 cytoplasm | IDA PMID:23585563 IOP1 protein is an external component of the human cytosolic... | KEEP AS NON CORE | Summary: Experimental cytoplasmic localization associated with the CIA machinery (CIAO1/CIAO2B/MMS19) that matures the FANCJ Fe-S cluster. Reason: A genuine cytoplasmic pool linked to Fe-S cluster maturation, but not the site of BRIP1's core DNA-repair function; retained as non-core. Supporting Evidence: PMID:23585563 IOP1 functions in the MMS19-dependent CIA pathway |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5684875 | ACCEPT | Summary: Reactome traceable-author-statement placing BRIP1 in the nucleoplasm within an HR/DSB-response reaction (ATR:ATRIP binding to RPA). Reason: Nucleoplasmic localization is correct; this is one of many Reactome pathway reactions annotating the same compartment. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5684882 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (CHEK1 recruitment reaction). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5684887 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (CHEK1 activation reaction). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685011 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (ATR activation reaction). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685156 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (ATR phosphorylates RPA2). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685341 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (BCDX2 stabilizes RAD51 filament). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685838 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (CX3 complex binds D-loops). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685985 | ACCEPT | Summary: Reactome TAS nucleoplasm localization; this reaction explicitly involves BRIP1 recruitment during long-range DSB resection (EXO1/DNA2 with BLM/WRN). Reason: Nucleoplasmic localization is correct and this reaction directly references BRIP1 recruitment in resection. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685994 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (long-range resection by EXO1/DNA2). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686410 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (BLM double-Holliday-junction dissolution). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686440 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (MUS81:EME1,EME2 cleaves D-loop). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686469 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (resolution of MUS81-cleaved D-loops). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686483 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (resolution of Holliday junctions). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686642 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (RAD52 single-strand annealing). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686657 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (ERCC1:XPF cleaves SSA flaps). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686663 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (completion of SSA). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693539 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (ligation/Holliday structure formation). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693542 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (RPA association with resected ssDNA). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693561 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (RAD51 binds BRCA2 at resected DSBs). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693564 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (RAD51 association with RAD52:DSB ends). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693580 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (RAD52 association with RPA complex). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693584 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (Holliday junction cleavage by GEN1/SLX). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693589 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (D-loop dissociation and strand annealing). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693593 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (D-loop extension by DNA polymerases). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693620 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (D-loop formation by PALB2/BRCA2/RAD51). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6799332 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (ATR phosphorylates TP53). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9701199 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (defective D-loop formation, BRCA1 LoF). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9704330 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (defective D-loop formation, PALB2 LoF). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9704408 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (defective D-loop formation, PALB2 binding). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9709571 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (BRCA2 RAD51-binding mutants). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9709601 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (defective BRCA2/RAD51 recruitment). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9853389 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (FIGNL1 binds RAD51). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9980006 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (ERCC1:XPF binds SSA intermediates). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9980021 | ACCEPT | Summary: Reactome TAS nucleoplasm localization (LIG1 binds SSA sites). Reason: Correct nucleoplasmic compartment for BRIP1. |
| GO:0005634 nucleus | IDA PMID:14504288 Cadmium induces nuclear export of Bach1, a transcriptional r... | ACCEPT | Summary: Nuclear localization annotation sourced from a paper on the UNRELATED bZIP transcription factor BACH1 (BTB and CNC homology 1; UniProt O14867), which shares the historical "BACH1" alias with BRIP1. Nuclear localization is nevertheless correct for BRIP1 from independent evidence. Reason: The term (nucleus) is correct for BRIP1 and abundantly supported by other references, so it is retained. However, this specific evidence line is mis-attributed: PMID:14504288 studies the transcription factor BACH1 (heme oxygenase-1 repressor), not the FANCJ helicase; the localization here is only coincidentally correct. See reference_review for PMID:14504288. Supporting Evidence: PMID:17596542 FANCJ colocalizes with RPA in nuclear foci after DNA damage |
| GO:0005737 cytoplasm | IDA PMID:14504288 Cadmium induces nuclear export of Bach1, a transcriptional r... | KEEP AS NON CORE | Summary: Cytoplasmic localization annotation sourced from the UNRELATED transcription factor BACH1 paper (PMID:14504288, cadmium-induced nuclear export of the HO-1 repressor Bach1). A cytoplasmic pool is independently documented for BRIP1 (CIA/Fe-S maturation), so the term is retained as non-core. Reason: The cytoplasm term is coincidentally correct for BRIP1 (documented CIA-related cytoplasmic pool, PMID:23585563), but the cited evidence (PMID:14504288) concerns the bZIP transcription factor BACH1, not FANCJ; the reference is mis-attributed via the shared alias. Kept as non-core with the correct supporting evidence. Supporting Evidence: PMID:23585563 IOP1 functions in the MMS19-dependent CIA pathway |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:14504288 Cadmium induces nuclear export of Bach1, a transcriptional r... | REMOVE | Summary: Annotation of transcriptional-regulation activity mis-mapped to BRIP1 from a paper on the UNRELATED bZIP transcription factor BACH1 (BTB and CNC homology 1; UniProt O14867), a transcriptional repressor of the heme oxygenase-1 (ho-1) gene. This function belongs to that other BACH1, not to the FANCJ helicase. Reason: PMID:14504288 ("Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene") is entirely about the bZIP/BTB transcription factor BACH1 (Bach1/small Maf heterodimers repressing ho-1, competition with Nrf2, Crm1/Exportin-1-dependent nuclear export). It contains no data on the BRIP1/FANCJ DNA helicase. BRIP1 is a DNA repair helicase with no established sequence-specific transcriptional-regulation function; this annotation is a gene-symbol conflation (the "BACH1" alias) and should be removed. Verified against the actual publication. Supporting Evidence: PMID:14504288 ho-1 is repressed by Bach1/small Maf heterodimers, it is activated by Nrf2/small Maf heterodimers |
| GO:0000077 DNA damage checkpoint signaling | NAS PMID:14576433 The BRCT domain is a phospho-protein binding domain. | KEEP AS NON CORE | Summary: Author-stated involvement in DNA damage checkpoint signaling. BRIP1 phosphorylation (Ser990) drives its cell-cycle-regulated BRCA1 interaction, and FANCJ contributes to the ICL-induced checkpoint/DDR. Reason: BRIP1 participates in the DNA damage response (e.g., 4N accumulation control after ICLs, acetylation-regulated end processing), so checkpoint involvement is plausible and supported, but it is downstream of / secondary to its core helicase and repair activities. Retained as non-core. Supporting Evidence: PMID:17581638 FANCJ helicase activity and MLH1 binding, but not BRCA1 binding, are essential to correct the FA-J cells' ICL-induced 4N DNA accumulation |
| GO:0003677 DNA binding | NAS PMID:15878853 Analysis of the DNA substrate specificity of the human BACH1... | ACCEPT | Summary: Author-stated DNA binding, from the study of BRIP1 DNA substrate specificity (preferential binding of forked duplex substrates). Reason: BRIP1 binds DNA as an intrinsic part of its helicase mechanism; directly supported by substrate-binding and sequestration assays. Supporting Evidence: PMID:15878853 BACH1 preferentially binds and unwinds a forked duplex substrate |
| GO:0003678 DNA helicase activity | NAS PMID:11301010 BACH1, a novel helicase-like protein, interacts directly wit... | ACCEPT | Summary: Author-stated DNA helicase activity from the original BACH1 discovery paper (a DEAH-family helicase-like protein interacting with BRCA1). Reason: Consistent with subsequently demonstrated biochemical helicase activity of BRIP1. Supporting Evidence: PMID:11301010 BACH1, a member of the DEAH helicase family |
| GO:0005515 protein binding | IPI PMID:11301010 BACH1, a novel helicase-like protein, interacts directly wit... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation for the direct BRIP1-BRCA1 interaction (partner BRCA1/P38398) from the original discovery paper. Reason: Generic MF term; the biologically central BRCA1 BRCT interaction is captured in core_functions and the DSB/HR annotations. Supporting Evidence: PMID:11301010 BACH1 binds directly to the BRCT repeats of BRCA1 |
| GO:0005515 protein binding | IPI PMID:14576433 The BRCT domain is a phospho-protein binding domain. | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (partner BRCA1/P38398) from the study showing BRCA1 BRCT is a phospho-peptide binding domain recognizing phospho-Ser990 of BRIP1. Reason: Generic MF term; the phosphorylation-dependent BRCA1 interaction is represented in core_functions. |
| GO:0005634 nucleus | NAS PMID:11301010 BACH1, a novel helicase-like protein, interacts directly wit... | ACCEPT | Summary: Author-stated nuclear localization from the original BACH1 discovery paper. Reason: BRIP1 is a nuclear protein; consistent with all experimental localization data. Supporting Evidence: PMID:17596542 FANCJ colocalizes with RPA in nuclear foci after DNA damage |
| GO:0006302 double-strand break repair | NAS PMID:11301010 BACH1, a novel helicase-like protein, interacts directly wit... | ACCEPT | Summary: Author-stated involvement in double-strand break repair; a catalytic-dead BRIP1 mutant interfered with DSB repair in a BRCA1-binding-dependent manner. Reason: Well supported: BRIP1 is required for efficient DSB repair via its BRCA1 association, a foundational finding for the gene. Supporting Evidence: PMID:11301010 interfered with normal double-strand break repair in a manner that was dependent on its BRCA1 binding function |
| GO:0036297 interstrand cross-link repair | IMP PMID:17581638 The FANCJ/MutLalpha interaction is required for correction o... | NEW | Summary: NEW annotation. BRIP1/FANCJ acts late in the Fanconi anemia interstrand crosslink (ICL) repair pathway; its helicase activity and MLH1 (MutLalpha) binding are required to correct the ICL-induced response of FA-J cells. This is arguably BRIP1's most disease-defining biological process yet is absent from the existing GOA set. Reason: Strongly supported: FANCJ-null (FA-J) cells accumulate 4N DNA and are hypersensitive to ICLs, corrected by wild-type FANCJ in a helicase- and MLH1-binding-dependent manner (PMID:17581638); FANCJ deficiency underlies Fanconi anemia group J and its cells are hypersensitive to crosslinking agents (UniProt DISEASE). Added to capture the ICL-repair process directly. Supporting Evidence: PMID:17581638 FANCJ helicase activity and MLH1 binding, but not BRCA1 binding, are essential to correct the FA-J cells' ICL-induced 4N DNA accumulation and sensitivity to ICLs PMID:18426915 the FA pathway has been classically described in terms of interstrand cross-link (ICL) repair |
| GO:0051539 4 iron, 4 sulfur cluster binding | IDA PMID:20639400 Fanconi anemia group J mutation abolishes its DNA repair fun... | NEW | Summary: NEW annotation. BRIP1 binds a [4Fe-4S] iron-sulfur cluster that is required for its helicase activity (Rad3/XPD-family Fe-S helicase). The pathogenic A349P substitution adjacent to a conserved Fe-S cysteine reduces bound iron and uncouples ATP hydrolysis from DNA unwinding. Reason: Experimentally supported cofactor-binding molecular function (UniProt COFACTOR "[4Fe-4S] cluster" with binding residues Cys283/Cys298/Cys310/Cys350; DOMAIN "4Fe-4S iron-sulfur-binding is required for helicase activity"). Present in the UniProt GO cross-references (as UniProtKB-KW) but missing from the GOA set; added because the Fe-S cluster is mechanistically and clinically central. Supporting Evidence: PMID:20639400 Purified recombinant FANCJ-A349P protein had reduced iron and was defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates |
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Download this section (compressed HTML)Q: What is the relative in vivo contribution of BRIP1's BRCA1-dependent HR role versus its BRCA1-independent, MLH1-dependent ICL-response role to genome stability and tumor suppression?
Q: Does BRIP1 have a physiological role in meiotic recombination in humans, consistent with its testis-enriched expression and the meiotic phenotypes of orthologs?
Experiment: Separation-of-function analysis in isogenic cells expressing BRIP1 variants that selectively disrupt BRCA1 binding, MLH1 binding, Fe-S cluster assembly, or catalytic activity, scored for ICL sensitivity, HR efficiency, G4 stability, and DPC repair.
Hypothesis: BRIP1's ICL-repair and HR roles are genetically separable and depend on distinct partner interactions rather than solely on helicase catalysis.
Experiment: Genome-wide mapping (e.g., CUT&RUN/ChIP) of BRIP1 occupancy at G-quadruplex-forming loci and replication-stress sites, correlated with fork progression and mutational signatures upon BRIP1 loss.
Hypothesis: BRIP1 is recruited to G4-forming and stalled-fork loci genome-wide, and its loss produces localized instability at these sites.
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