id: Q9NPI8
gene_symbol: FANCF
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FANCF is a subunit of the Fanconi anemia (FA) nuclear core complex, a
  multisubunit ubiquitin ligase that also contains FANCA, FANCB, FANCC, FANCE,
  FANCG, FANCL (the RING E3), FANCM and associated FAAP proteins. The core
  complex is activated by DNA damage, particularly DNA interstrand cross-links
  (ICLs) and replication stress, and its essential output is monoubiquitination
  of the FANCD2-FANCI (ID2) heterodimer. Monoubiquitinated ID2 is loaded onto
  chromatin near the lesion and directs the downstream steps of replication-
  coupled ICL repair (nucleolytic unhooking, translesion synthesis and
  homologous recombination), thereby maintaining chromosome stability. FANCF
  has no catalytic activity or recognizable sequence motif; its C-terminal
  domain adopts a HEAT/ARM-like helical-repeat fold and it acts as a flexible
  molecular adaptor/scaffold that bridges the FANCA:FANCG and FANCC:FANCE
  subcomplexes, so it is required for assembly and stability of the intact core
  complex and hence for FANCD2 monoubiquitination. FANCF is predominantly
  nuclear/nucleoplasmic and associates with chromatin upon DNA damage. Biallelic
  loss-of-function of FANCF causes Fanconi anemia complementation group F, with
  bone marrow failure, congenital malformations, cancer predisposition and
  cellular hypersensitivity to cross-linking agents.
existing_annotations:
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      FANCF, as a subunit of the FA core complex, participates in the cellular
      response to DNA damage (ICLs and replication stress). Correct but broad;
      the specific process is interstrand cross-link repair.
    action: ACCEPT
    reason: >-
      Well supported by phylogenetic inference and by direct evidence that the
      FA core complex is activated by DNA damage to monoubiquitinate FANCD2-FANCI.
      A valid parent term; retained as a general process alongside the more
      specific ICL repair annotation.
    supported_by:
    - reference_id: PMID:17082180
      supporting_text: >-
        At least eight FA proteins (FANCA, B, C, E, F, G, L, and M) form a
        nuclear core complex required for monoubiquitination of a downstream
        protein, FANCD2.
    - reference_id: PMID:21915857
      supporting_text: >-
        they showed an aberrant response to DNA cross-linking agents as manifested
        by G(2) arrest, chromosomal aberrations, reduced survival, and an inability
        to monoubiquitinate FANCD2.
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      FANCF is a bona fide subunit of the Fanconi anemia nuclear (core) complex.
      This is its core cellular-component annotation.
    action: ACCEPT
    reason: >-
      Directly demonstrated: FANCF complexes with FANCA, FANCC and FANCG in the
      nucleus, and is a stable component of the eight-subunit FA core complex
      resolved by cryo-EM. Phylogenetic (IBA) call agrees with experimental data.
    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: >-
      FANCF localizes predominantly to the nucleus, consistent with its role in
      the nuclear FA core complex.
    action: ACCEPT
    reason: >-
      UniProt subcellular-location mapping agrees with experimental
      immunofluorescence/fractionation showing predominant nuclear localization.
      Broad but correct (the more granular nucleoplasm term is also annotated).
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      FANCF is required for the FA pathway that repairs DNA interstrand
      cross-links. Core biological process.
    action: ACCEPT
    reason: >-
      The InterPro2GO mapping (FANCF family IPR035428 to ICL repair) is
      biologically correct: the FA core complex, of which FANCF is an essential
      adaptor subunit, drives FANCD2 monoubiquitination that is required for
      replication-coupled ICL repair.
    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: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: >-
      Automated (ARBA/InterPro) call that FANCF is part of the FA nuclear
      complex; duplicates the experimentally supported membership annotation.
    action: ACCEPT
    reason: >-
      Consistent with experimental and phylogenetic evidence for FA core complex
      membership. Redundant with the IBA/IDA/NAS annotations to the same term but
      not incorrect.
    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:11063725
  qualifier: enables
  review:
    summary: >-
      IPI capturing FANCF interactions with FANCA (O15360) and FANCG (O15287),
      the core-complex partners it bridges. 'Protein binding' is uninformative;
      the underlying function is molecular adaptor/scaffold activity.
    action: MODIFY
    reason: >-
      These interactions are exactly the adaptor function of FANCF: it bridges
      the FANCA:FANCG and FANCC:FANCE subcomplexes to assemble the core complex.
      Replace the uninformative 'protein binding' with protein-macromolecule adaptor
      activity (GO:0030674), which captures the actual molecular function.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: >-
        FANCF was found predominantly in the nucleus, where it complexes with
        FANCA, FANCC and FANCG.
    - reference_id: PMID:17082180
      supporting_text: >-
        The human FANCF protein reportedly functions as a molecular adaptor
        within the FA nuclear complex, bridging between the subcomplexes A:G and
        C:E.
    - reference_id: PMID:15262960
      supporting_text: >-
        Our data demonstrate that FANCF acts as a flexible adaptor protein that
        plays a key role in the proper assembly of the FA core complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12649160
  qualifier: enables
  review:
    summary: >-
      Yeast two/three-hybrid mapping of the FANCF-FANCG (and FANCA) contacts.
      As with the other core-complex interaction, the informative molecular
      function is adaptor activity, not the generic 'protein binding'.
    action: MODIFY
    reason: >-
      The mapped FANCF/FANCG contact and FANCG-mediated bridging of FANCA to
      FANCF are the physical basis of FANCF's scaffolding role. Modify to
      protein-macromolecule adaptor activity (GO:0030674).
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    supported_by:
    - reference_id: PMID:12649160
      supporting_text: >-
        FANCG was shown to interact with both the amino-terminus of FANCA and
        the carboxyl-terminal region of FANCF.
    - reference_id: PMID:12649160
      supporting_text: >-
        FANCG was able to mediate interaction between FANCA and FANCF
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      High-throughput binary interactome (HuRI) Y2H hit between FANCF and TCP11
      (Q8WWU5-7). Real recorded interaction but uninformative and with no
      established relevance to FANCF function.
    action: KEEP_AS_NON_CORE
    reason: >-
      A systematic all-by-all Y2H screen; the interaction is not corroborated by
      focused studies and TCP11 has no known role in the FA pathway. Retain as a
      documented interaction but it is non-core and 'protein binding' carries no
      functional information.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        Here we present a human 'all-by-all' reference interactome map of human
        binary protein interactions, or 'HuRI'.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      Y2H hit between FANCF and HTT (huntingtin, P42858) from a
      neurodegeneration-focused interactome screen. Real recorded interaction but
      uninformative and of no established relevance to FANCF function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Large-scale screen aimed at neurodegenerative-disease proteins; the FANCF-
      HTT interaction is not supported by focused FA-pathway studies. Retain as a
      documented interaction but mark non-core; 'protein binding' is
      uninformative as a molecular function.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: >-
        systematic yeast two-hybrid interaction screening of ∼500 ND-related
        proteins and integration of literature interactions
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence (HPA) localizes FANCF to the nucleoplasm, consistent
      with its role in the nuclear FA core complex.
    action: ACCEPT
    reason: >-
      Direct immunofluorescence evidence agrees with the predominant nuclear
      localization reported for endogenous FANCF and the core complex.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:22343915
  qualifier: located_in
  review:
    summary: >-
      The FA core complex (including FANCF) is loaded onto chromatin in response
      to DNA damage; ComplexPortal-curated chromatin localization.
    action: ACCEPT
    reason: >-
      Consistent with DNA-damage-induced chromatin recruitment of the FA core
      complex, which is required for functional integrity of the FA-BRCA pathway.
      Experimental IDA assigned by ComplexPortal for the complex FANCF belongs to.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: >-
        is 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: >-
      FANCF, via the FA core complex and FANCD2-FANCI monoubiquitination,
      contributes to replication-dependent DNA interstrand cross-link repair.
    action: ACCEPT
    reason: >-
      The cited work establishes that the FA pathway (FANCI-FANCD2) is required
      for replication-coupled ICL repair; FANCF is an essential upstream core-
      complex subunit for that pathway. Core biological process (duplicates the
      IEA ICL-repair annotation).
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: >-
        The Fanconi anemia pathway promotes replication-dependent DNA interstrand
        cross-link repair.
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: NAS
  original_reference_id: PMID:22343915
  qualifier: part_of
  review:
    summary: >-
      Curator statement (ComplexPortal) that FANCF is part of the FA nuclear
      core complex. Consistent with all other membership evidence.
    action: ACCEPT
    reason: >-
      FANCF is an integral subunit of the FA nuclear core complex characterized
      in this and related studies. Redundant with the experimental IDA and IBA
      annotations to the same term but correct.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: Fanconi anemia (FA) nuclear core complex is a multiprotein complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835411
  qualifier: located_in
  review:
    summary: >-
      Reactome models a cytosolic FA-core-complex:HSP70 species that binds PKR
      (PKR-mediated signaling). FANCF is predominantly nuclear, so a cytosolic
      pool is peripheral and less well established.
    action: KEEP_AS_NON_CORE
    reason: >-
      Derived from a Reactome PKR-signaling reaction rather than direct FANCF
      localization data. Retained (author-traceable) but marked non-core because
      FANCF's characterized localization and function are nuclear; any cytosolic
      role is minor and not central to FA-pathway ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785126
  qualifier: located_in
  review:
    summary: >-
      Reactome ICL-repair reaction (FA core complex assembles at ICLs) placing
      FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the predominant nuclear/nucleoplasmic localization of FANCF
      and the FA core complex acting at ICLs in the nucleoplasm.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785342
  qualifier: located_in
  review:
    summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear/nucleoplasmic localization of the FA core
      complex during ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785361
  qualifier: located_in
  review:
    summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear/nucleoplasmic localization of the FA core
      complex during ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear/nucleoplasmic localization of the FA core
      complex during ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear/nucleoplasmic localization of the FA core
      complex during ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786155
  qualifier: located_in
  review:
    summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear/nucleoplasmic localization of the FA core
      complex during ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786166
  qualifier: located_in
  review:
    summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear/nucleoplasmic localization of the FA core
      complex during ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786171
  qualifier: located_in
  review:
    summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear/nucleoplasmic localization of the FA core
      complex during ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788385
  qualifier: located_in
  review:
    summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear/nucleoplasmic localization of the FA core
      complex during ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788392
  qualifier: located_in
  review:
    summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Consistent with the nuclear/nucleoplasmic localization of the FA core
      complex during ICL repair.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: FANCF was found predominantly in the nucleus
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:20347428
  qualifier: part_of
  review:
    summary: >-
      Experimental (IDA) demonstration that FANCF is part of the FA core complex,
      here shown to associate with the FANCM-MHF DNA-remodeling complex that
      promotes FANCD2 monoubiquitination.
    action: ACCEPT
    reason: >-
      Direct experimental membership evidence; FANCF is an integral subunit of
      the FA core complex, consistent with all other lines of evidence. Core
      cellular-component annotation.
    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
core_functions:
- description: >-
    Acts as a flexible molecular adaptor/scaffold within the Fanconi anemia
    nuclear core complex, bridging the FANCA:FANCG and FANCC:FANCE subcomplexes
    to assemble and stabilize the complex; this scaffolding is required for the
    complex's monoubiquitination of FANCD2-FANCI and thus for replication-coupled
    DNA interstrand cross-link repair and chromosome stability.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor 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:17082180
    supporting_text: >-
      The human FANCF protein reportedly functions as a molecular adaptor within
      the FA nuclear complex, bridging between the subcomplexes A:G and C:E.
  - reference_id: PMID:17082180
    supporting_text: >-
      Two C-terminal loops of FANCF are essential for monoubiquitination of
      FANCD2 and normal cellular resistance to the DNA cross-linking agent
      mitomycin C.
  - reference_id: PMID:11063725
    supporting_text: >-
      FANCF was found predominantly in the nucleus, where it complexes with
      FANCA, FANCC and FANCG.
  - reference_id: PMID:15262960
    supporting_text: >-
      We found that the C terminus of FANCF interacts directly with FANCG and
      allows the assembly of other FA proteins into a stable complex.
  - reference_id: PMID:15262960
    supporting_text: >-
      The N terminus appears to stabilize the interaction with FANCA and FANCG
      and is essential for the binding of the FANCC/FANCE subcomplex.
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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11063725
  title: The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC
    and FANCG.
  findings:
  - statement: >-
      FANCF is predominantly nuclear and forms a complex with FANCA, FANCC and
      FANCG; these interactions are lost in FA cell lines, indicating each subunit
      is required for complex formation.
    supporting_text: >-
      FANCF was found predominantly in the nucleus, where it complexes with FANCA,
      FANCC and FANCG.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified primary paper (de Winter 2000, Hum Mol Genet). Establishes
      nuclear localization and FA core-complex membership of FANCF; directly
      supports the FA nuclear complex and nucleus/nucleoplasm annotations.
- id: PMID:12649160
  title: 'Fanconi anemia protein complex: mapping protein interactions in the yeast
    2- and 3-hybrid systems.'
  findings:
  - statement: >-
      FANCG binds both the N-terminus of FANCA and the C-terminal region of FANCF,
      and can bridge FANCA to FANCF, mapping the physical architecture underlying
      FANCF's adaptor role.
    supporting_text: >-
      FANCG was shown to interact with both the amino-terminus of FANCA and the
      carboxyl-terminal region of FANCF.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Gordon & Buchwald 2003, Blood). Y2H/Y3H mapping of FANCF-
      FANCG/FANCA contacts; supports the molecular adaptor function.
- id: PMID:15262960
  title: The Fanconi anemia gene product FANCF is a flexible adaptor protein.
  findings:
  - statement: >-
      FANCF is a flexible adaptor whose C-terminus binds FANCG to nucleate
      assembly of the other FA proteins, while its N-terminus stabilizes the
      FANCA/FANCG interaction and is required to recruit the FANCC/FANCE
      subcomplex; FANCF does not have a ROM-like function.
    supporting_text: >-
      We found that the C terminus of FANCF interacts directly with FANCG and
      allows the assembly of other FA proteins into a stable complex.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified primary paper (Leveille 2004, JBC). Mutagenesis study that
      first established FANCF as a flexible adaptor bridging the FANCA:FANCG and
      FANCC:FANCE subcomplexes; the primary experimental basis for the molecular
      adaptor activity core function and the subcomplex-bridging model.
- id: PMID:17082180
  title: Structural determinants of human FANCF protein that function in the assembly
    of a DNA damage signaling complex.
  findings:
  - statement: >-
      The FANCF C-terminal domain has a Cand1-like helical-repeat fold and
      functions as a molecular adaptor bridging the A:G and C:E subcomplexes; two
      C-terminal loops are essential for FANCD2 monoubiquitination and mitomycin C
      resistance.
    supporting_text: >-
      The human FANCF protein reportedly functions as a molecular adaptor within
      the FA nuclear complex, bridging between the subcomplexes A:G and C:E.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Kowal 2007, JBC). Crystal structure + mutagenesis defining
      FANCF as a molecular adaptor whose C-terminal surface assembles the core
      complex and is required for FANCD2 monoubiquitination. Primary basis for the
      protein-macromolecule adaptor activity core function.
- id: PMID:19965384
  title: The Fanconi anemia pathway promotes replication-dependent DNA interstrand
    cross-link repair.
  findings:
  - statement: >-
      FANCI-FANCD2 (activated by the FA core complex) is required for
      replication-coupled ICL repair in S phase, including incisions and
      translesion synthesis.
    supporting_text: >-
      FANCI-FANCD2 is required for replication-coupled ICL repair in S phase.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Knipscheer 2009, Science). Establishes the FA pathway's role
      in replication-dependent ICL repair; NAS basis for the FANCF ICL-repair
      process annotation.
- id: PMID:20347428
  title: A histone-fold complex and FANCM form a conserved DNA-remodeling complex
    to maintain genome stability.
  findings:
  - statement: >-
      FANCM-MHF associates with the FA core complex and promotes FANCD2
      monoubiquitination in response to DNA damage.
    supporting_text: >-
      FANCM-MHF associates with the Fanconi anemia (FA) core complex, promotes
      FANCD2 monoubiquitination in response to DNA damage
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Yan 2010, Mol Cell). Focuses on FANCM-MHF but characterizes
      the FA core complex; IDA basis for FANCF FA-nuclear-complex membership.
- id: PMID:21915857
  title: Fancf-deficient mice are prone to develop ovarian tumours.
  findings:
  - statement: >-
      Fancf-deficient cells show an aberrant response to DNA cross-linking agents
      (G2 arrest, chromosomal aberrations, reduced survival, inability to
      monoubiquitinate FANCD2), providing in vivo confirmation that FANCF is
      required for FANCD2 activation and the DNA cross-link damage response.
    supporting_text: >-
      they showed an aberrant response to DNA cross-linking agents as manifested
      by G(2) arrest, chromosomal aberrations, reduced survival, and an inability
      to monoubiquitinate FANCD2.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Bakker 2012, J Pathol). Fancf knockout mouse model; in vivo
      corroboration that FANCF loss abolishes FANCD2 monoubiquitination and confers
      cross-linker hypersensitivity, supporting the DNA damage response / ICL
      repair process annotations. Mouse, not human, so recorded as MEDIUM relevance.
- 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:
  - statement: >-
      FAAP20 is an integral FA core-complex protein whose UBZ domain is required
      for DNA-damage-induced chromatin loading of FANCA and functional integrity of
      the FA pathway.
    supporting_text: >-
      is required for DNA-damage-induced chromatin loading of FANCA and the
      functional integrity of the FA pathway
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Ali 2012, Blood). Supports DNA-damage-induced chromatin
      recruitment of the FA core complex; basis for FANCF chromatin and FA-nuclear-
      complex (NAS) annotations assigned by ComplexPortal.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Luck 2020, Nature; HuRI). Large-scale binary Y2H; the FANCF-
      TCP11 hit is uninformative and non-core.
- 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: VERIFIED
    review_notes: >-
      PubMed-verified (Haenig 2020, Cell Rep). Neurodegeneration-focused Y2H; the
      FANCF-HTT hit is uninformative and non-core.
- 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: []
suggested_questions:
- question: >-
    Does FANCF have any function outside the FA core complex (e.g. the cytosolic
    FA-core-complex:HSP70:PKR species modeled by Reactome), or is it strictly a
    nuclear scaffolding subunit?
- question: >-
    Are the high-throughput FANCF interactions with TCP11 and HTT biologically
    meaningful, or are they interactome-screen artifacts?
suggested_experiments:
- hypothesis: >-
    Each subcomplex-bridging contact on the FANCF C-terminal adaptor surface
    contributes independently to core-complex assembly and FANCD2
    monoubiquitination.
  description: >-
    Structure-guided separation-of-function mutations in the FANCF C-terminal
    adaptor surface (e.g. the loops mutated in PMID:17082180), assayed for
    core-complex assembly and FANCD2 monoubiquitination.
- hypothesis: FANCF localization and interactions are restricted to the nucleus/chromatin.
  description: >-
    Proximity labeling (BioID/TurboID) of endogenous FANCF in unperturbed vs
    ICL-damaged cells to define its complete interaction/localization landscape
    and test for any non-nuclear pool.