id: O15287
gene_symbol: FANCG
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FANCG (also known as XRCC9) is a 622-residue tetratricopeptide-repeat (TPR) protein
  that forms an all-alpha-helical solenoid and is a subunit of the multiprotein Fanconi
  anemia (FA) core complex (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM,
  together with FAAP20/FAAP100/FAAP24). The FA core complex is a nuclear, chromatin-associated
  E3 ubiquitin ligase (with FANCL as the catalytic RING subunit) that, in response to
  DNA damage and replication stress, monoubiquitinates the FANCD2-FANCI heterodimer to
  promote repair of DNA interstrand crosslinks during S phase and to channel lesions into
  translesion synthesis and homologous recombination. FANCG itself has no known catalytic
  or DNA-binding activity; it acts as a protein-protein adaptor/scaffold, binding FANCA
  directly and being required for the assembly, stability and nuclear accumulation of the
  core complex. Loss of FANCG causes chromosomal instability, hypersensitivity to
  crosslinking agents (e.g. mitomycin C) and Fanconi anemia complementation group G, a
  bone-marrow-failure and cancer-predisposition syndrome. Beyond the nuclear core complex,
  FANCG participates in a phosphorylation(Ser7)-dependent complex with BRCA2/FANCD1, FANCD2
  and XRCC3, and a minor fraction localizes to mitochondria where it interacts with
  peroxiredoxin-3 (PRDX3) and influences resistance to oxidative stress.
existing_annotations:
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      FANCG is a subunit of the FA core complex that acts within the cellular response to
      DNA damage / replication stress; the phylogenetically inferred DNA damage response
      annotation is well supported and captures a core biological role.
    action: ACCEPT
    reason: >-
      The FA core complex is required for DNA damage recognition at stalled replication forks
      and for the damage-induced monoubiquitination of FANCD2-FANCI. FANCG is one of the eight
      core subunits and FANCG-deficient cells are defective in the DNA damage response,
      consistent with this IBA call at an appropriate level of generality.
    supported_by:
    - reference_id: PMID:22266823
      supporting_text: >-
        Eight of the FA proteins comprise the FA core complex, a multisubunit complex required
        for DNA damage recognition at a stalled replication fork
    - reference_id: PMID:9256465
      supporting_text: >-
        that partially corrected the hypersensitivity of UV40 to mitomycin C, cisplatin, ethyl
        methanesulfonate, UV, and
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      FANCG is a bona fide subunit of the FA nuclear core complex; this is the best-supported
      cellular-component annotation and represents a core function.
    action: ACCEPT
    reason: >-
      Multiple independent experimental studies place FANCG in the multiprotein nuclear FA core
      complex with FANCA, FANCC, FANCE, FANCF, FANCL and FANCM. The phylogenetic (IBA) call is
      concordant with this experimental consensus.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: >-
        FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and
        FANCG
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      The major form of FANCG is nuclear, where it functions as part of the FA core complex;
      the electronic subcellular-location annotation is correct though generic.
    action: ACCEPT
    reason: >-
      UniProt records the major form as nuclear (minor form cytoplasmic), and FANCG operates in
      a nuclear FA complex. Nucleus is a correct if broad location; more specific nucleoplasm and
      chromatin annotations also exist.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: >-
        FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and
        FANCG
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      A minor cytoplasmic form of FANCG is documented, but the functionally important pool is
      nuclear; the cytoplasm location is retained as a non-core localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      UniProt notes that the minor form is cytoplasmic, and FANCA/FANCG are reported to be
      cytoplasmic in G1 and G2-M and nuclear during S phase. The annotation is not wrong but is
      peripheral to the core nuclear ICL-repair function.
    supported_by:
    - reference_id: PMID:17060495
      supporting_text: >-
        FANCA and FANCG are cytoplasmic in G1 and G2-M phase but are predominantly nuclear during
        S phase
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to DNA damage response; concordant with the IBA and with
      experimental evidence for FANCG in the FA damage-response pathway.
    action: ACCEPT
    reason: >-
      Duplicates the well-supported DNA damage response role (see the IBA row). The electronic
      inference is at an appropriate level and is not an over-annotation.
    supported_by:
    - reference_id: PMID:22266823
      supporting_text: >-
        the FA proteins cooperate in a DNA damage response (DDR) pathway required for DNA
        interstrand crosslink repair
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      FANCG, as a core-complex subunit required for FANCD2 monoubiquitination, is required for
      replication-coupled interstrand crosslink repair; this is a core biological process.
    action: ACCEPT
    reason: >-
      InterPro-based electronic annotation matches the experimental consensus that the FA pathway
      promotes replication-dependent ICL repair and that FANCG-null cells are hypersensitive to
      crosslinkers.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: >-
        FANCI-FANCD2 is required for replication-coupled ICL repair in S phase
    - reference_id: PMID:9256465
      supporting_text: >-
        that partially corrected the hypersensitivity of UV40 to mitomycin C, cisplatin
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: >-
      Electronic (InterPro) assignment of FANCG to the FA nuclear complex, concordant with
      experimental IDA/IBA/NAS evidence.
    action: ACCEPT
    reason: >-
      Duplicates the experimentally well-established FA nuclear complex membership; the InterPro
      family model correctly maps FANCG into the complex.
    supported_by:
    - reference_id: PMID:22266823
      supporting_text: >-
        Eight of the FA proteins comprise the FA core complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10627486
  qualifier: enables
  review:
    summary: >-
      FANCG binds FANCA strongly (yeast two-hybrid). This is a biologically central interaction
      that underlies FANCG's scaffold role, but the generic 'protein binding' term is
      uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The FANCA-FANCG interaction is real and functionally important (it seeds core-complex
      assembly), but GO:0005515 does not convey the adaptor/scaffold function. The informative
      molecular function is captured by a proposed NEW protein-macromolecule adaptor activity term
      and in core_functions.
    supported_by:
    - reference_id: PMID:10627486
      supporting_text: >-
        the authors found a strong interaction between FANCA and FANCG proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10652215
  qualifier: enables
  review:
    summary: >-
      Yeast two-hybrid mapping of FA protein interactions (FANCA partner). Real interaction but
      uninformative MF term; retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supports FANCG's participation in the FA protein-interaction network (FANCA), but the
      generic protein binding term does not describe FANCG's molecular activity.
    supported_by:
    - reference_id: PMID:10652215
      supporting_text: Investigation of Fanconi anemia protein interactions by yeast two-hybrid analysis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11063725
  qualifier: enables
  review:
    summary: >-
      FANCG complexes with FANCA, FANCC and FANCF in the nucleus (IntAct rows for FANCA and FANCF).
      Central to complex assembly but uninformative as an MF term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Documents FANCG-FANCA and FANCG-FANCF interactions within the nuclear FA complex; complex
      membership is better captured by the FA nuclear complex CC term, and the scaffold activity by
      core_functions.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: >-
        FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and
        FANCG
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12649160
  qualifier: enables
  review:
    summary: >-
      Yeast 2-/3-hybrid mapping of FA complex protein interactions (FANCA, FANCF partners). Real
      but uninformative MF; kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Corroborates FANCG interactions within the FA complex; the generic term does not describe a
      molecular activity.
    supported_by:
    - reference_id: PMID:12649160
      supporting_text: 'Fanconi anemia protein complex: mapping protein interactions in the yeast'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Proteome-scale interactome mapping capturing a FANCG-FANCA interaction; retained as
      non-core given the uninformative MF term.
    action: KEEP_AS_NON_CORE
    reason: >-
      The FANCA partner is biologically plausible and consistent with complex membership, but
      protein binding is uninformative and high-throughput.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: Towards a proteome-scale map of the human protein-protein interaction network
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17289582
  qualifier: enables
  review:
    summary: >-
      Interaction detected in the study identifying FAAP24 as an FA core-complex protein
      interacting with FANCM (FANCA partner row); retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with FANCG being embedded in the FA core complex, but the generic MF term is
      uninformative.
    supported_by:
    - reference_id: PMID:17289582
      supporting_text: Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17396147
  qualifier: enables
  review:
    summary: >-
      Interaction detected in the FAAP100 study (FANCA partner). Consistent with core-complex
      membership; non-core due to uninformative MF term.
    action: KEEP_AS_NON_CORE
    reason: >-
      FAAP100 is essential for FA-pathway activation and this row supports FANCG's presence in the
      complex, but protein binding conveys no molecular activity.
    supported_by:
    - reference_id: PMID:17396147
      supporting_text: FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19102630
  qualifier: enables
  review:
    summary: >-
      FANCG binds the SH3 domain of alphaII-spectrin (SPTAN1) via an SH3-binding motif. A specific,
      documented interaction but peripheral to the core FA-complex function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Direct, mapped interaction (SH3-binding motif in FANCG), proposed to stabilize alphaII-spectrin
      for ICL repair. Real but a secondary scaffold interaction; the MF term itself is uninformative.
    supported_by:
    - reference_id: PMID:19102630
      supporting_text: >-
        The site of interaction in FANCG was mapped to a motif that binds to SH3 domains and contains
        a consensus sequence with preference for the SH3 domain of alphaIISp
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22458338
  qualifier: enables
  review:
    summary: >-
      Interaction with HTLV Tax reported in a host-pathogen interactome screen; not a physiological
      human FANCG function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This IntAct row is a xeno (viral Tax) interaction from a large host-pathogen mapping effort and
      does not inform FANCG's endogenous molecular function.
    supported_by:
    - reference_id: PMID:22458338
      supporting_text: Host-pathogen interactome mapping for HTLV-1 and -2 retroviruses
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Interaction (FANCA partner) from a large-scale interactome/protein-communities study; consistent
      with complex membership, retained non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      FANCA partner is plausible and matches known biology, but the term is uninformative and the
      evidence is high-throughput.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities and disease networks
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31467278
  qualifier: enables
  review:
    summary: >-
      Binary interactome mapping capturing a FANCG-FANCA interaction (isoform O15360-3); retained as
      non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with FANCA binding but uninformative as a molecular function and high-throughput.
    supported_by:
    - reference_id: PMID:31467278
      supporting_text: Maximizing binary interactome mapping with a minimal number of assays
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Rows from a reference binary interactome map pairing FANCG with several unrelated proteins
      (SUOX, ZNF329, TPRX1, TCEANC, CCHCR1, PRPF18); these are non-specific high-throughput hits.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The partners in this screen are not part of the FA pathway and no functional relationship is
      established; treated as over-annotation of the generic protein-binding term.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      A neurodegeneration protein-aggregation interactome screen linking FANCG to many unrelated
      proteins (VIM, GFAP, CYP3A4, RAB5A, HSPB1, etc.); mostly non-specific aggregation-driven hits.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Aside from FANCA, the partners are not FA-pathway related and the assay context (widespread
      protein aggregation) is prone to non-specific associations; over-annotation of protein binding.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: >-
        Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers
        Widespread Protein Aggregation in Affected Brains
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      BioPlex dual proteome-scale network capturing a FANCG-FANCA interaction; retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      FANCA partner is consistent with known biology, but the term is uninformative and evidence is
      high-throughput.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37398436
  qualifier: enables
  review:
    summary: >-
      FANCG-FANCA interaction reported within an AI-guided PPI drug-discovery pipeline; consistent
      with complex membership, retained non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      The FANCA partner is plausible, but the generic term is uninformative and the study context is
      unrelated to FANCG's function.
    supported_by:
    - reference_id: PMID:37398436
      supporting_text: AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      FANCG-FANCA interaction from a multimodal cell-maps study; retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with FANCA binding/complex membership, but protein binding is uninformative as an MF.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional genomics
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IPI
  original_reference_id: PMID:10627486
  qualifier: enables
  review:
    summary: >-
      Proposed informative molecular function to replace the uninformative 'protein binding' rows: FANCG
      is a TPR scaffold that binds FANCA directly and acts as an adaptor bridging FANCA into the FA core
      complex, required for complex assembly, stability and nuclear accumulation.
    action: NEW
    reason: >-
      FANCG has no catalytic or DNA-binding activity; its molecular role within the FA core complex is that
      of a protein-protein adaptor/scaffold. The strong direct FANCA-FANCG interaction, together with
      FANCG's requirement for FANCA stability/nuclear localization and for core-complex integrity, supports
      an adaptor activity that better captures FANCG's molecular function than GO:0005515.
    supported_by:
    - reference_id: PMID:10627486
      supporting_text: the authors found a strong interaction between FANCA and FANCG proteins
    - reference_id: PMID:11063725
      supporting_text: a model in which a multi-protein FA complex serves a nuclear function to maintain genomic integrity
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence localizes FANCG to nuclear speckles; a specific sub-nuclear location that
      is peripheral to the core chromatin-associated FA-complex function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The nuclear speck localization comes from a single immunofluorescence dataset and does not
      correspond to the established chromatin/replication-fork site of FA-complex action; retained as a
      non-core location rather than removed.
    supported_by:
    - reference_id: GO_REF:0000052
      supporting_text: Gene Ontology annotation based on curation of immunofluorescence data
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:22343915
  qualifier: located_in
  review:
    summary: >-
      The FA core complex (including FANCA, stabilized by FANCG) is loaded onto chromatin in a
      DNA-damage-induced manner; chromatin localization is a core-relevant location for FANCG.
    action: ACCEPT
    reason: >-
      Damage-induced chromatin loading of the FA core complex is central to FA-pathway activation, and
      the ComplexPortal IDA annotation reflects the functional site of action.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: >-
        required for DNA-damage-induced chromatin loading of FANCA and the functional integrity of the
        FA pathway
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: NAS
  original_reference_id: PMID:19965384
  qualifier: involved_in
  review:
    summary: >-
      Interstrand crosslink repair is a core FANCG process; the NAS annotation is supported by the
      demonstration that the FA pathway drives replication-coupled ICL repair.
    action: ACCEPT
    reason: >-
      FANCG is required for FANCD2/FANCI monoubiquitination, which the cited work shows is required for
      replication-coupled ICL repair; ICL repair is the canonical FA-pathway function.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: NAS
  original_reference_id: PMID:22343915
  qualifier: part_of
  review:
    summary: >-
      FANCG is a subunit of the FA nuclear core complex; NAS annotation concordant with the
      experimental consensus.
    action: ACCEPT
    reason: >-
      The FAAP20 study characterizes the FA nuclear core complex of which FANCG is an integral subunit.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: FAAP20 is an integral component of the FA nuclear core complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835411
  qualifier: located_in
  review:
    summary: >-
      Reactome places a FA core complex:HSP70 species (binding PKR) in the cytosol; corresponds to the
      minor cytoplasmic pool of FANCG rather than its core nuclear function.
    action: KEEP_AS_NON_CORE
    reason: >-
      A minor cytoplasmic/cytosolic form of FANCG exists and is captured by this Reactome cytosolic
      reaction, but the functionally central pool is nuclear/chromatin-associated.
    supported_by:
    - reference_id: PMID:17060495
      supporting_text: >-
        FANCA and FANCG are cytoplasmic in G1 and G2-M phase but are predominantly nuclear during
        S phase
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785126
  qualifier: located_in
  review:
    summary: >-
      Reactome localizes FANCG to the nucleoplasm as part of FA-pathway ICL-repair reactions; a correct
      core location for the nuclear FA complex.
    action: ACCEPT
    reason: >-
      Nucleoplasm is consistent with the nuclear FA core complex acting on chromatin/DNA in the ICL-repair
      pathway modeled by Reactome.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785342
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm localization within the FA ICL-repair pathway; correct core location.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear FA core complex; duplicate of the nucleoplasm annotation from another
      Reactome reaction in the same pathway.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785361
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm localization (Monoubiquitination of FANCD2:FANCI reaction); correct core location.
    action: ACCEPT
    reason: Consistent with the nuclear FA core complex acting in the ICL-repair pathway.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm localization within the FA ICL-repair pathway; correct core location.
    action: ACCEPT
    reason: Consistent with the nuclear FA core complex; Reactome pathway localization.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm localization within the FA ICL-repair pathway; correct core location.
    action: ACCEPT
    reason: Consistent with the nuclear FA core complex; Reactome pathway localization.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786155
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm localization within the FA ICL-repair pathway; correct core location.
    action: ACCEPT
    reason: Consistent with the nuclear FA core complex; Reactome pathway localization.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786166
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm localization within the FA ICL-repair pathway; correct core location.
    action: ACCEPT
    reason: Consistent with the nuclear FA core complex; Reactome pathway localization.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786171
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm localization (FANCD2 deubiquitination by USP1:WDR48); correct core location.
    action: ACCEPT
    reason: Consistent with the nuclear FA core complex; Reactome pathway localization.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788385
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm localization within the FA ICL-repair pathway; correct core location.
    action: ACCEPT
    reason: Consistent with the nuclear FA core complex; Reactome pathway localization.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788392
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm localization within the FA ICL-repair pathway; correct core location.
    action: ACCEPT
    reason: Consistent with the nuclear FA core complex; Reactome pathway localization.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:22266823
  qualifier: part_of
  review:
    summary: >-
      Direct experimental identification of FANCG within the FA core complex; core cellular-component
      annotation.
    action: ACCEPT
    reason: >-
      The study defines the eight-subunit FA core complex (including FANCG) and its role in FANCD2/FANCI
      monoubiquitination and Rev1 regulation.
    supported_by:
    - reference_id: PMID:22266823
      supporting_text: Eight of the FA proteins comprise the FA core complex, a multisubunit complex required for DNA damage recognition at a stalled replication fork
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:22343915
  qualifier: part_of
  review:
    summary: Direct identification of FANCG in the FA nuclear core complex; core cellular-component annotation.
    action: ACCEPT
    reason: >-
      FAAP20 is characterized as an integral component of the FA nuclear core complex, which includes FANCG;
      supports core-complex membership.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: FAAP20 is an integral component of the FA nuclear core complex
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:22705371
  qualifier: part_of
  review:
    summary: >-
      FANCG identified within the FA core complex in the study linking RNF8 ubiquitin signaling to the FA
      network via FAAP20; core CC annotation.
    action: ACCEPT
    reason: >-
      The work characterizes FAAP20 as a component of the FA core complex (which contains FANCG) recruited
      to interstrand crosslinks.
    supported_by:
    - reference_id: PMID:22705371
      supporting_text: mediated by FAAP20, a component of the FA core complex
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:20347428
  qualifier: part_of
  review:
    summary: >-
      FANCM-MHF associates with the FA core complex (containing FANCG) and promotes FANCD2
      monoubiquitination; supports core-complex membership.
    action: ACCEPT
    reason: >-
      The DNA-remodeling FANCM-MHF module is shown to associate with the vertebrate FA core complex, of
      which FANCG is a subunit.
    supported_by:
    - reference_id: PMID:20347428
      supporting_text: FANCM-MHF associates with the Fanconi anemia (FA) core complex, promotes FANCD2 monoubiquitination in response to DNA damage
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17060495
  qualifier: enables
  review:
    summary: >-
      FANCG physically interacts with the mitochondrial peroxidase peroxiredoxin-3 (PRDX3); a specific but
      non-core interaction linked to oxidative-stress resistance rather than the nuclear FA pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      The wild-type (but not G546R) FANCG-PRDX3 interaction is well documented by Y2H and co-IP, but it
      reflects a secondary mitochondrial/oxidative-stress role; the generic protein binding term is also
      uninformative as an MF.
    supported_by:
    - reference_id: PMID:17060495
      supporting_text: Wild-type but not G546R mutant FANCG physically interacts with the mitochondrial peroxidase peroxiredoxin-3 (PRDX3)
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:17060495
  qualifier: located_in
  review:
    summary: >-
      A fraction of FANCG localizes to mitochondria (immunofluorescence, subcellular fractionation).
      Experimentally supported but a minor/secondary localization relative to the core nuclear function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Immunofluorescence and mitochondrial-fractionation data support a mitochondrial pool of FANCG, but
      this is a moonlighting localization tied to oxidative-stress biology and not the canonical
      chromatin-associated FA-complex function.
    supported_by:
    - reference_id: PMID:17060495
      supporting_text: both the immunofluorescent and Western blot assays are consistent with a portion of FANCG protein localizing to the mitochondria
- term:
    id: GO:0007005
    label: mitochondrion organization
  evidence_type: IMP
  original_reference_id: PMID:17060495
  qualifier: involved_in
  review:
    summary: >-
      FA-G mutant cells show distorted mitochondrial structures, implicating FANCG in mitochondrial
      integrity; a secondary role likely downstream of oxidative-stress/PRDX3 biology.
    action: KEEP_AS_NON_CORE
    reason: >-
      The IMP is based on abnormal mitochondrial morphology in FANCG-deficient cells (via PRDX3
      deregulation). It is experimentally supported and retained, but is peripheral to the core nuclear
      ICL-repair function rather than a primary FANCG activity.
    supported_by:
    - reference_id: PMID:17060495
      supporting_text: FA-G cells demonstrate distorted mitochondrial structures
- term:
    id: GO:0003684
    label: damaged DNA binding
  evidence_type: TAS
  original_reference_id: PMID:9806548
  qualifier: enables
  review:
    summary: >-
      FANCG has no established intrinsic DNA-binding activity; this old TAS/ProtInc molecular-function
      annotation appears to attribute a complex-level property to the wrong subunit and is best treated as
      an over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      FANCG is a TPR alpha-solenoid scaffold lacking any known DNA-binding domain; within the FA core
      complex, DNA/branched-structure binding is contributed by the FANCM-MHF module, not FANCG. The cited
      reference (the FANCG=XRCC9 identification paper) makes no claim of direct damaged-DNA binding, and the
      annotation derives from a legacy ProtInc mapping. Per curation guidance this is not removed outright
      (a TAS from the era of poorly-defined FA-protein function), but flagged as an over-annotation of a
      subunit that does not itself enable damaged DNA binding.
    supported_by:
    - reference_id: PMID:9806548
      supporting_text: We identified the gene as human XRCC9
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: TAS
  original_reference_id: PMID:9256465
  qualifier: involved_in
  review:
    summary: >-
      FANCG (XRCC9) is required for DNA repair, as its expression corrects the mutagen hypersensitivity and
      chromosomal instability of the repair-deficient CHO UV40 mutant; a correct core process (general parent
      of interstrand cross-link repair).
    action: ACCEPT
    reason: >-
      The original XRCC9 cloning study established a DNA-repair role by functional complementation. DNA repair
      is a correct if broad process term; the more specific interstrand cross-link repair term is also annotated.
    supported_by:
    - reference_id: PMID:9256465
      supporting_text: that partially corrected the hypersensitivity of UV40 to mitomycin C, cisplatin, ethyl methanesulfonate, UV, and
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: ISS
  original_reference_id: PMID:12861027
  qualifier: involved_in
  review:
    summary: >-
      FANCG is required for efficient homologous-recombination repair of DNA double-strand
      breaks. FANCG-knockout DT40 cells show ~9-fold reduced HR repair of I-SceI-induced
      chromosomal DSBs, and FANCG additionally nucleates a Ser7-phosphorylation-dependent
      D1-D2-G-X3 complex (BRCA2/FANCD1, FANCD2, XRCC3) that supports HR repair.
    action: NEW
    reason: >-
      This is a genuine, experimentally supported FANCG function that the GOA set did not
      capture as a distinct process annotation. Both supporting studies are in CHICKEN DT40
      cells, so the evidence code is ISS rather than IMP - an IMP would assert a human mutant
      phenotype that neither reference provides. Gene disruption in DT40 directly demonstrates
      a requirement for FANCG in HR-mediated DSB repair (PMID:12861027), and FANCG-dependent,
      Ser7-phosphorylation-gated assembly of the D1-D2-G-X3 complex with the RAD51 paralog
      XRCC3 links FANCG to the HR machinery independently of its core-complex role in FANCD2
      monoubiquitination (PMID:18212739). Treated as a secondary (non-core) function relative
      to the canonical core-complex ICL-repair role.
    supported_by:
    - reference_id: PMID:12861027
      supporting_text: We conclude that FANCG is required for efficient HR-mediated repair of at least some types of DSBs
    - reference_id: PMID:18212739
      supporting_text: >-
        A role for D1-D2-G-X3 in homologous recombination repair (HRR) is supported by our
        finding that FANCG and the RAD51-paralog XRCC3 are epistatic for sensitivity to DNA
        crosslinking compounds in DT40 chicken cells
core_functions:
- description: >-
    FANCG is a tetratricopeptide-repeat (TPR) scaffold subunit of the nuclear Fanconi anemia core
    complex. It binds FANCA directly and, as a protein-protein adaptor, is required for the assembly,
    stability and nuclear accumulation of the eight-subunit core complex. The intact core complex acts
    as an E3 ubiquitin ligase (catalyzed by the FANCL RING subunit) that monoubiquitinates the
    FANCD2-FANCI heterodimer on chromatin in response to DNA damage/replication stress, thereby driving
    replication-coupled DNA interstrand crosslink repair (and coordinating downstream translesion
    synthesis and homologous recombination). FANCG has no intrinsic catalytic or DNA-binding activity;
    whether it contributes more than structural stabilization (e.g. substrate presentation) to the E3
    ligase reaction is unresolved.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  contributes_to_molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  directly_involved_in:
  - id: GO:0036297
    label: interstrand cross-link repair
  - id: GO:0006974
    label: DNA damage response
  locations:
  - id: GO:0005654
    label: nucleoplasm
  - id: GO:0000785
    label: chromatin
  in_complex:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  supported_by:
  - reference_id: PMID:10627486
    supporting_text: the authors found a strong interaction between FANCA and FANCG proteins
  - reference_id: PMID:22266823
    supporting_text: Eight of the FA proteins comprise the FA core complex, a multisubunit complex required for DNA damage recognition at a stalled replication fork
  - reference_id: PMID:11063725
    supporting_text: a model in which a multi-protein FA complex serves a nuclear function to maintain genomic integrity
  - reference_id: PMID:19965384
    supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase
proposed_new_terms: []
suggested_questions:
- question: >-
    What is the precise molecular contribution of the FANCG TPR scaffold to core-complex E3 ligase activity
    beyond stabilizing FANCA (e.g. does it position substrates or other subunits)?
- question: >-
    Is the Ser7-phosphorylation-dependent FANCG-BRCA2/FANCD2/XRCC3 complex a genuinely separable
    homologous-recombination function, or a hand-off from the core complex?
- question: >-
    How physiologically important is the mitochondrial/PRDX3 oxidative-stress role of FANCG relative to its
    nuclear ICL-repair function in the bone-marrow-failure phenotype?
suggested_experiments:
- description: >-
    Structure-guided separation-of-function FANCG mutants (FANCA-binding vs core-complex-stabilizing
    surfaces) assayed for FANCD2 monoubiquitination and MMC/cisplatin resistance.
  experiment_type: structure-function mutagenesis
- description: >-
    Quantitative proteomics of the FANCG interactome under DNA-damage vs oxidative-stress conditions to
    delineate nuclear core-complex partners from mitochondrial/other secondary partners.
  experiment_type: affinity-proteomics
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
    accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:10627486
  title: Strong FANCA/FANCG but weak FANCA/FANCC interaction in the yeast 2-hybrid system.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes the direct, strong FANCA-FANCG interaction that underlies FANCG's
      scaffold role in the core complex.
- id: PMID:10652215
  title: Investigation of Fanconi anemia protein interactions by yeast two-hybrid analysis.
  findings: []
- id: PMID:11063725
  title: The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified. Directly supports nuclear FA-complex membership of FANCG with FANCA, FANCC and FANCF.
- id: PMID:12649160
  title: 'Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems.'
  findings: []
- id: PMID:12861027
  title: Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand
    breaks by homologous recombination in vertebrate cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text verified (PMC165738). FANCG-knockout DT40 cells show ~9-fold reduced HR repair of
      I-SceI-induced chromosomal DSBs; establishes FANCG's requirement for efficient HR-mediated
      DSB repair (basis for the added GO:0000724 annotation).
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:17060495
  title: Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full-text verified. Supports a secondary mitochondrial/PRDX3 oxidative-stress role and mitochondrial
      localization of FANCG (basis for the mitochondrion and mitochondrion-organization annotations, judged
      non-core).
- id: PMID:17289582
  title: Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.
  findings: []
- id: PMID:17396147
  title: FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway.
  findings: []
- id: PMID:18212739
  title: FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2
    and XRCC3.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract verified. FANCG (via Ser7 phosphorylation) promotes the D1-D2-G-X3 complex
      (BRCA2/FANCD1, FANCD2, XRCC3) supporting HR repair, a core-complex-independent role;
      corroborates the added HR-repair annotation.
- id: PMID:19102630
  title: The SH3 domain of alphaII spectrin is a target for the Fanconi anemia protein, FANCG.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Verified. Maps a direct FANCG SH3-binding motif to alphaII-spectrin; a specific but non-core scaffold
      interaction.
- id: PMID:19965384
  title: The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified. Establishes that the FA pathway (FANCD2/FANCI monoubiquitination, dependent on the FANCG-
      containing core complex) drives replication-coupled ICL repair.
- id: PMID:20347428
  title: A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability.
  findings: []
- id: PMID:22266823
  title: Regulation of Rev1 by the Fanconi anemia core complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text verified. Defines the eight-subunit FA core complex and shows FANCG (like FANCA) is required
      for error-prone TLS/point mutagenesis; anchors the core-complex and DNA-damage-response roles.
- id: PMID:22343915
  title: 'FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required for functional integrity
    of the FA-BRCA DNA repair pathway.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified. Supports FA nuclear core complex membership and DNA-damage-induced chromatin loading of the
      complex.
- id: PMID:22458338
  title: Host-pathogen interactome mapping for HTLV-1 and -2 retroviruses.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Verified as a host-pathogen screen; the FANCG-Tax (viral) interaction is not a physiological human
      function and does not inform FANCG's endogenous role.
- id: PMID:22705371
  title: A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA
    repair network.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:31467278
  title: Maximizing binary interactome mapping with a minimal number of assays.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput binary interactome map; FANCG partners here (SUOX, ZNF329, etc.) are not FA-pathway
      related and are treated as over-annotation of the generic protein-binding term.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread
    Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Aggregation-prone interactome screen; the many non-FA partners reported for FANCG are likely
      non-specific and are treated as over-annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:37398436
  title: AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:9256465
  title: The human XRCC9 gene corrects chromosomal instability and mutagen sensitivities in CHO UV40 cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text verified. Original XRCC9/FANCG cloning by functional complementation; establishes the DNA
      repair / chromosomal-stability role.
- id: PMID:9806548
  title: The Fanconi anaemia group G gene FANCG is identical with XRCC9.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: MISCITED
    review_notes: >-
      Correct identifier for the FANCG=XRCC9 identification paper, but it is used in GOA to support a
      'damaged DNA binding' molecular function that the paper does not claim; cited here only to document
      that over-annotation.
- id: Reactome:R-HSA-6785126
  title: FA core complex assembles at DNA interstrand crosslinks (ICLs)
  findings: []
- id: Reactome:R-HSA-6785342
  title: FANCD2:FANCI complex and UBE2T bind ICL-DNA associated with the FA core complex
  findings: []
- id: Reactome:R-HSA-6785361
  title: Monoubiquitination of FANCD2:FANCI
  findings: []
- id: Reactome:R-HSA-6785732
  title: DNA nucleases bind monoubiquitinated ID2 complex
  findings: []
- id: Reactome:R-HSA-6785986
  title: DNA nucleases unhook the interstrand crosslink (ICL)
  findings: []
- id: Reactome:R-HSA-6786155
  title: POLN binds ICL-DNA
  findings: []
- id: Reactome:R-HSA-6786166
  title: Translesion synthesis across unhooked ICL by POLN
  findings: []
- id: Reactome:R-HSA-6786171
  title: FANCD2 deubiquitination by USP1:WDR48
  findings: []
- id: Reactome:R-HSA-6788385
  title: The complex of ATR and ATRIP is recruited to ICL-DNA
  findings: []
- id: Reactome:R-HSA-6788392
  title: ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA
  findings: []
- id: Reactome:R-HSA-9835411
  title: FA core complex:HSP70s binds PKR
  findings: []