id: Q8NB91
gene_symbol: FANCB
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Fanconi anemia group B protein (FANCB, also FAAP95) is a non-catalytic subunit of the
  Fanconi anemia (FA) core complex, a nuclear multisubunit ubiquitin ligase that, in
  response to DNA replication stress and interstrand crosslinks (ICLs), monoubiquitinates
  the FANCD2-FANCI (ID2) heterodimer to activate the FA/BRCA DNA repair pathway. FANCB
  assembles with the RING E3 ligase FANCL and with FAAP100 into the FANCB-FANCL-FAAP100
  (BL100) catalytic module, where it serves as the central scaffold and dimerization
  factor: two BL100 heterotrimers associate through FANCB to form the symmetric
  "dimer of trimers" that gives the core complex its architecture and positions the two
  FANCL RING domains to ubiquitinate FANCD2 and FANCI. FANCB is required for the
  stability and coordinated nuclear import of the module (chaperoned by FANCA and FANCM)
  and for chromatin loading of the complex at sites of damage; in its absence FANCD2
  monoubiquitination fails. The gene is X-linked (Xp22.31) and subject to X-inactivation,
  so a single active copy is functional, making FANCB a dosage-sensitive node whose loss
  causes Fanconi anemia complementation group B, frequently a severe VACTERL-with-hydrocephalus
  phenotype, with cellular hypersensitivity to crosslinking agents and chromosomal
  instability.
existing_annotations:
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: FANCB is a core structural subunit of the Fanconi anemia nuclear (core) complex.
    action: ACCEPT
    reason: >-
      This is the defining, best-supported complex-membership annotation for FANCB and is
      corroborated experimentally (IDA, NAS below) and structurally. FANCB is one of the eight
      stably associated subunits of the FA core complex and, with FANCL and FAAP100, forms its
      central catalytic module.
    supported_by:
    - reference_id: PMID:15502827
      supporting_text: essential component of the nuclear protein
    - reference_id: PMID:31666700
      supporting_text: A dimer of FANCB-FAAP100 heterodimers is located in the middle region of the structure
- term:
    id: GO:1905168
    label: positive regulation of double-strand break repair via homologous recombination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that the FA pathway promotes homologous-recombination
      repair of double-strand breaks.
    action: KEEP_AS_NON_CORE
    reason: >-
      Promotion of HR is a genuine but downstream, pathway-level consequence of FA-core-complex
      activity rather than FANCB's direct molecular function. FANCB's core role is architectural
      scaffolding of the BL100 module that enables FANCD2-FANCI monoubiquitination; effects on
      HR are indirect and shared across FA proteins. Retained as non-core.
    supported_by:
    - reference_id: PMID:21458466
      supporting_text: Gene targeting efficiency was 16.2% (6/37) for control cells and 0% (0/96) for fancbΔex2
- term:
    id: GO:1990414
    label: replication-born double-strand break repair via sister chromatid exchange
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) inference linking FANCB to repair of replication-associated
      double-strand breaks via sister-chromatid exchange.
    action: KEEP_AS_NON_CORE
    reason: >-
      The FA core complex modulates sister-chromatid-exchange outcomes at stalled/blocked
      replication forks, but this is a downstream pathway-level role rather than FANCB's
      direct scaffolding activity. Retained as non-core.
    supported_by:
    - reference_id: PMID:20347428
      supporting_text: FANCM-MHF associates with the Fanconi anemia (FA) core complex
    - reference_id: PMID:21458466
      supporting_text: Decreased Homologous RecombinationThe fancbΔex2 cells were tested for spontaneous sister chromatid exchanges (SCEs)
- term:
    id: GO:2000042
    label: negative regulation of double-strand break repair via homologous recombination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that the FA pathway also restrains homologous recombination.
    action: KEEP_AS_NON_CORE
    reason: >-
      The FA pathway both promotes and limits HR/crossover outcomes (fork protection, suppression
      of aberrant recombination and sister-chromatid exchange). This regulatory role is downstream
      and pathway-level, not FANCB's direct molecular function. Retained as non-core.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: FANCB localizes to the nucleus, where the FA core complex acts on chromatin.
    action: ACCEPT
    reason: >-
      Consistent with UniProt subcellular location (Nucleus) and with the more specific
      nucleoplasm and Fanconi anaemia nuclear complex annotations. Nuclear import of the
      BL100 module is chaperoned by FANCA/FANCM. Broad but correct.
    supported_by:
    - reference_id: PMID:17396147
      supporting_text: each member of the L-B-P100 subcomplex has a disturbed nuclear localization in FA-A cells
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: FANCB participates in DNA interstrand crosslink repair as part of the FA core complex.
    action: ACCEPT
    reason: >-
      This is the central biological process of the FA pathway. FANCB is required for the
      FANCD2-FANCI monoubiquitination step that activates replication-coupled ICL repair.
      Correct and specific.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase
    - reference_id: PMID:32106311
      supporting_text: the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: FANCB is a subunit of the Fanconi anemia nuclear (core) complex (InterPro-based).
    action: ACCEPT
    reason: >-
      Consistent with the experimental IDA/NAS and phylogenetic IBA annotations of the same
      term; FANCB (IPR033333) is a defining FA core complex component.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17396147
  qualifier: enables
  review:
    summary: >-
      Binary interaction evidence (with FAAP100, Q0VG06). "Protein binding" is uninformative;
      the underlying, well-supported molecular function is a protein-macromolecule adaptor /
      scaffold activity.
    action: MODIFY
    reason: >-
      The IPI captures the direct FANCB-FAAP100 interaction, but GO:0005515 conveys no specific
      function. Structural and biochemical work shows FANCB is the dimerization/scaffold factor
      that bridges FANCL and FAAP100 into the BL100 module and templates core-complex assembly,
      stimulating FANCL ligase activity. This is best represented as protein-macromolecule
      adaptor activity (GO:0030674).
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    supported_by:
    - reference_id: PMID:17396147
      supporting_text: directly interacts with FANCB and FANCL to form a stable subcomplex
    - reference_id: PMID:27986592
      supporting_text: FANCB plays a key structural function, being the dimerization factor
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:22343915
  qualifier: located_in
  review:
    summary: FANCB, as part of the FA core complex, is loaded onto chromatin upon DNA damage.
    action: ACCEPT
    reason: >-
      Experimental (IDA) chromatin localization is consistent with the DNA-damage-induced
      chromatin loading of the FA core complex, which delivers the FANCD2-FANCI substrate
      to damaged chromatin. Defer to the curator's experimental assessment.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: required for DNA-damage-induced chromatin loading of FANCA
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: NAS
  original_reference_id: PMID:19965384
  qualifier: involved_in
  review:
    summary: FANCB contributes to interstrand crosslink repair via the FA pathway.
    action: ACCEPT
    reason: >-
      Duplicate of the ICL-repair process term (also IEA) supported by an authoritative
      statement that the FA pathway (FANCI-FANCD2 monoubiquitination, which FANCB enables)
      drives replication-coupled ICL repair. Correct and central.
    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: FANCB is an integral component of the FA nuclear core complex.
    action: ACCEPT
    reason: >-
      Consistent with the IDA/IEA/IBA annotations of the same term. The FAAP20 study treats
      FANCB as an established FA nuclear core-complex subunit.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835411
  qualifier: located_in
  review:
    summary: >-
      A cytosolic pool of FANCB exists as the assembled BL100 module prior to chaperoned
      nuclear import (and in the FA-core-complex:HSP70 assembly implicated in PKR signaling).
    action: ACCEPT
    reason: >-
      The BL100 (L-B-P100) module is the major cytosolic form of FANCL/FANCB/FAAP100 and moves
      to the nucleus only when associated with FANCA and FANCM. Cytosolic localization is thus
      biologically accurate for an assembly/storage pool, though FANCB's functional site is nuclear.
    supported_by:
    - reference_id: PMID:17396147
      supporting_text: each member of the L-B-P100 subcomplex has a disturbed nuclear localization in FA-A cells
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785126
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: >-
      Nucleoplasm is the functional compartment of the assembled FA core complex; consistent
      with the nucleus and Fanconi anaemia nuclear complex annotations.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785342
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: Redundant Reactome nucleoplasm localization; correct functional compartment.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785361
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: Redundant Reactome nucleoplasm localization; correct functional compartment.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: Redundant Reactome nucleoplasm localization; correct functional compartment.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: Redundant Reactome nucleoplasm localization; correct functional compartment.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786155
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: Redundant Reactome nucleoplasm localization; correct functional compartment.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786166
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: Redundant Reactome nucleoplasm localization; correct functional compartment.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786171
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: Redundant Reactome nucleoplasm localization; correct functional compartment.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788385
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: Redundant Reactome nucleoplasm localization; correct functional compartment.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788392
  qualifier: located_in
  review:
    summary: FANCB acts in the nucleoplasm as part of the FA core complex during ICL repair.
    action: ACCEPT
    reason: Redundant Reactome nucleoplasm localization; correct functional compartment.
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:20347428
  qualifier: part_of
  review:
    summary: >-
      Experimental (IDA) evidence places FANCB in the FA nuclear core complex, which the
      FANCM-MHF DNA-remodeling complex associates with.
    action: ACCEPT
    reason: >-
      Direct experimental complex-membership annotation consistent with all other GO:0043240
      annotations. The full study biochemically purified the FA core complex (of which FANCB
      is a subunit); defer to the curator's experimental determination.
    supported_by:
    - reference_id: PMID:20347428
      supporting_text: FANCM-MHF associates with the Fanconi anemia (FA) core complex
core_functions:
- description: >-
    Central scaffold and dimerization subunit of the FANCB-FANCL-FAAP100 (BL100) catalytic
    module of the Fanconi anemia core complex. FANCB bridges and dimerizes two BL100
    heterotrimers, templating assembly of the symmetric core complex and stimulating the
    FANCL RING E3 ligase to monoubiquitinate the FANCD2-FANCI complex during replication-coupled
    interstrand crosslink repair.
  supported_by:
  - reference_id: PMID:27986592
    supporting_text: leaving the FANCB subunit as the sole candidate for the dimerization element of the BL100 complex
  - reference_id: PMID:27986592
    supporting_text: its mono-ubiquitination function is stimulated by 6-fold in the presence of FANCB and FAAP100
  - reference_id: PMID:31666700
    supporting_text: deletion of FANCB, FANCL or FAAP100, that comprise the catalytic module and the structural scaffold for the complex
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  directly_involved_in:
  - id: GO:0036297
    label: interstrand cross-link repair
  locations:
  - id: GO:0005654
    label: nucleoplasm
  in_complex:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
proposed_new_terms: []
suggested_questions:
- question: >-
    Does FANCB self-associate to form the dimerization interface directly, or is the
    "dimer of trimers" bridged through FANCB-FAAP100 contacts (isolated FANCB self-association
    has not been demonstrated)?
- question: >-
    How does hemizygous/X-inactivation dosage of the single active FANCB allele set the
    threshold for FA core complex assembly and FANCD2 monoubiquitination?
suggested_experiments:
- description: >-
    Structure-guided mutagenesis of the FANCB dimerization interface to test whether disrupting
    BL100 dimerization abolishes FANCD2-FANCI monoubiquitination while preserving individual
    subunit stability.
- description: >-
    Quantitative reconstitution of FANCL ubiquitin-ligase activity with and without FANCB to
    dissect its architectural (adaptor) versus allosteric stimulation of catalysis.
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: PMID:15502827
  title: X-linked inheritance of Fanconi anemia complementation group B.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding paper identifying FANCB (FAAP95) as an essential FA core-complex subunit required
      for FANCD2 monoubiquitination and establishing X-linkage at Xp22.31. Directly supports the
      complex-membership and function annotations.
- id: PMID:16116422
  title: A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi
    anemia complementation group M.
  findings: []
- id: PMID:17396147
  title: FAAP100 is essential for activation of the Fanconi anemia-associated DNA
    damage response pathway.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Shows FAAP100 directly interacts with FANCB and FANCL to form the stable L-B-P100 (BL100)
      subcomplex, protecting members from degradation and coordinating nuclear import. Basis for
      the FANCB IPI and the adaptor/scaffold reinterpretation.
- id: PMID:19965384
  title: The Fanconi anemia pathway promotes replication-dependent DNA interstrand
    cross-link repair.
  findings: []
- id: PMID:20347428
  title: A histone-fold complex and FANCM form a conserved DNA-remodeling complex
    to maintain genome stability.
  findings: []
- id: PMID:21458466
  title: The phenotype of FancB-mutant mouse embryonic stem cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      FancB-mutant mouse ES cells show MMC hypersensitivity, chromosomal instability, absent
      MMC-induced FancD2 foci, reduced Rad51 foci, abolished gene targeting (0/96 vs 16.2% in
      controls), and reduced spontaneous SCEs. Provides direct experimental support for the
      FANCD2-monoubiquitination requirement and the (non-core) HR/SCE-promotion annotations.
- 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: []
- id: PMID:27986592
  title: The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric
    Mono-ubiquitination of FANCI-FANCD2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cryo-EM of the BL100 catalytic module identifies FANCB as the sole dimerization element,
      forming a dimer of FANCB-FANCL-FAAP100 heterotrimers that stimulates FANCL activity ~6-fold.
      Primary support for the protein-macromolecule adaptor/scaffold core function.
- id: PMID:31666700
  title: Structure of the Fanconi anaemia monoubiquitin ligase complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full FA core complex structure; a central dimer of FANCB-FAAP100 heterodimers forms the
      structural scaffold, and deletion of FANCB/FANCL/FAAP100 (the catalytic module/scaffold)
      eliminates activity. Supports the scaffold/architecture core function.
- id: PMID:32106311
  title: Association of clinical severity with FANCB variant type in Fanconi anemia.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Genotype-phenotype study using transcript analysis, genetic complementation, and
      biochemical reconstitution of FANCD2 monoubiquitination. Establishes FANCB as
      indispensable for the enzymatic activation of FANCD2 monoubiquitination in ICL repair,
      with residual activity of missense variants correlating with clinical severity.
- id: PMID:32939280
  title: Deep learning enables the atomic structure determination of the Fanconi Anemia
    core complex from cryoEM.
  findings: []
- 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: []