Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0043240 Fanconi anaemia nuclear complex	IBA GO_REF:0000033	ACCEPT	Summary: FANCA is a core structural subunit of the multiprotein FA nuclear (core) complex. This is the central, well-established cellular-component annotation for FANCA and is supported phylogenetically, electronically, and by multiple experimental studies. Reason: FANCA is definitively a component of the FA core complex (FANCA/B/C/E/F/G/L/M plus FAAP proteins), which monoubiquitinates FANCD2-FANCI. The IBA call is consistent with direct experimental evidence. Supporting Evidence: PMID:12649160 proteins form a nuclear complex required for the monoubiquination of the
GO:0045589 regulation of regulatory T cell differentiation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic (PANTHER/GO_Central) inference seeded from a mouse Fanca annotation (MGI:1341823). This reflects a peripheral/pleiotropic immunological role rather than the core DNA-repair scaffolding function of FANCA. Reason: FA proteins have been implicated in immune phenotypes in mouse models, so this is not clearly wrong, but regulation of regulatory T cell differentiation is not a core molecular activity of a DNA interstrand-crosslink-repair core-complex subunit. It is a context-specific, non-core process derived from a single ortholog annotation.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: FANCA localizes to the nucleus, which is the compartment where the functional FA core complex acts. Electronic mapping from the UniProt subcellular-location vocabulary is consistent with experimental data. Reason: The major, functional form of FANCA is nuclear (UniProt SUBCELLULAR LOCATION; the FAA-FAC complex is found in the nucleus). Correct location annotation. Supporting Evidence: PMID:9398857 is found in similar abundance in both cytoplasm and nucleus
GO:0005737 cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: A minor pool of FANCA is cytoplasmic; unbound FANCA/FANCC localize predominantly to the cytoplasm before assembly/nuclear import. This represents a non-core (inactive/pre-assembly) location rather than the functional nuclear site of action. Reason: UniProt notes the major form is nuclear and the minor form cytoplasmic. Cytoplasmic localization is real but is not where FANCA performs its DNA-repair function; keep as non-core. Supporting Evidence: PMID:9398857 unbound FAA and FAC localize predominantly to the cytoplasm, the FAA-FAC complex
GO:0036297 interstrand cross-link repair	IEA GO_REF:0000002	ACCEPT	Summary: FANCA is a core-complex subunit essential for the FA pathway that repairs DNA interstrand crosslinks via monoubiquitination of FANCD2-FANCI. This is a core biological process for FANCA. Reason: InterPro2GO mapping (IPR003516, FANCA family) to interstrand cross-link repair is biologically accurate and matches experimental and pathway knowledge. Supporting Evidence: PMID:19965384 central event in the activation of the Fanconi anemia pathway is the
GO:0043240 Fanconi anaemia nuclear complex	IEA GO_REF:0000002	ACCEPT	Summary: Electronic (InterPro) support for FANCA membership in the FA nuclear complex, consistent with the IBA/IDA/NAS evidence. Reason: Correct and central cellular-component annotation; FANCA is a defining subunit of the FA core complex.
GO:0005515 protein binding	IPI PMID:10627486 Strong FANCA/FANCG but weak FANCA/FANCC interaction in the y...	MARK AS OVER ANNOTATED	Summary: Yeast two-hybrid interaction between FANCA and FANCG. FANCA-FANCG is one of the strongest and most direct interactions within the FA core complex, but the GO term captured (protein binding) is uninformative. Reason: The underlying interaction is real and biologically meaningful (FANCA-FANCG), but GO:0005515 protein binding is an uninformative molecular-function term. FANCA's scaffold/adaptor role is captured in core_functions. Supporting Evidence: PMID:10627486 found a strong interaction between FANCA and FANCG proteins
GO:0005515 protein binding	IPI PMID:10652215 Investigation of Fanconi anemia protein interactions by yeas...	MARK AS OVER ANNOTATED	Summary: Yeast two-hybrid evidence for a strong, direct FANCA-FANCG interaction. Real interaction but uninformative MF term. Reason: GO:0005515 protein binding is uninformative. The FANCA-FANCG interaction is captured in the description/core_functions as part of the core-complex scaffold. Supporting Evidence: PMID:10652215 indicating strong, direct interaction between these proteins
GO:0005515 protein binding	IPI PMID:11063725 The Fanconi anemia protein FANCF forms a nuclear complex wit...	MARK AS OVER ANNOTATED	Summary: FANCA co-complexes with FANCC, FANCF and FANCG in the nucleus. Real complex membership but annotated only as generic protein binding. Reason: Uninformative MF term; the FANCA-FANCF/FANCG/FANCC associations are core-complex relationships better captured by the FA nuclear complex CC annotation and core_functions. Supporting Evidence: PMID:11063725 where it complexes with FANCA, FANCC and
GO:0005515 protein binding	IPI PMID:12649160 Fanconi anemia protein complex: mapping protein interactions...	MARK AS OVER ANNOTATED	Summary: Yeast two/three-hybrid mapping showing FANCG interacts with the amino-terminus of FANCA and that FANCG bridges FANCA-FANCF. Real interactions, uninformative MF term. Reason: GO:0005515 protein binding is uninformative; the mapped FANCA-FANCG/FANCF contacts define core-complex architecture and are captured elsewhere. Supporting Evidence: PMID:12649160 FANCG was shown to interact with both
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: Large-scale (proteome-scale) human protein-protein interaction mapping; the recorded FANCA partner is FANCG. High-throughput evidence for generic protein binding. Reason: High-throughput interactome data annotated as generic protein binding is uninformative for molecular function. The FANCA-FANCG interaction itself is already well established.
GO:0005515 protein binding	IPI PMID:17289582 Identification of FAAP24, a Fanconi anemia core complex prot...	MARK AS OVER ANNOTATED	Summary: Study identifying FAAP24 as an FA core-complex protein that (via FANCM) links the complex to damaged DNA; the recorded FANCA interactant here is FANCG. Annotated as generic protein binding. Reason: The interaction is genuine core-complex biology, but GO:0005515 is uninformative. Captured in core_functions/CC annotations.
GO:0005515 protein binding	IPI PMID:17396147 FAAP100 is essential for activation of the Fanconi anemia-as...	MARK AS OVER ANNOTATED	Summary: FAAP100 (and FANCG) interactions; FAAP100 is essential for activation of the FA DNA-damage-response pathway and is an integral core-complex protein. Annotated as generic protein binding. Reason: Real core-complex interaction but uninformative MF term. FANCA's role as an interaction hub is captured in core_functions. Supporting Evidence: PMID:17396147 FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage
GO:0005515 protein binding	IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote...	MARK AS OVER ANNOTATED	Summary: SH3-domain peptide-array screen recording a FANCA-GRB2 interaction. This is a systematic domain-ligand screen, peripheral to FANCA's core function. Reason: High-throughput peptide-array interaction annotated as generic protein binding; uninformative and peripheral (GRB2 is not part of the FA core complex).
GO:0005515 protein binding	IPI PMID:22266823 Regulation of Rev1 by the Fanconi anemia core complex.	MARK AS OVER ANNOTATED	Summary: FAAP20 (Q6NZ36) binds directly to the FANCA subunit and is required for stability of the core complex and FANCD2 monoubiquitination. Direct and functionally important, but annotated as generic protein binding. Reason: The FANCA-FAAP20 interaction is direct and biologically central, but GO:0005515 is uninformative. FANCA's role as the FAAP20 docking subunit is captured in core_functions. Supporting Evidence: PMID:22266823 multisubunit Fanconi anemia core complex. FAAP20 binds to FANCA subunit and is
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Architecture-of-the-human-interactome study; recorded FANCA partner is FANCG. High-throughput protein binding. Reason: High-throughput interactome evidence annotated as generic protein binding is uninformative for molecular function.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Interactome-mapping study (neurodegenerative-disease network); recorded FANCA partner is FANCG. High-throughput protein binding. Reason: High-throughput interactome data annotated as generic protein binding; uninformative MF term.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Dual proteome-scale interaction network (BioPlex); recorded FANCA partner is FANCG. High-throughput protein binding. Reason: High-throughput interactome evidence annotated as generic protein binding; uninformative MF term.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: OpenCell endogenous-tagging cartography; recorded FANCA partner is FAAP100. High-throughput protein binding consistent with core-complex membership. Reason: High-throughput proteomics annotated as generic protein binding; uninformative MF term although the FAAP100 association is consistent with the known complex.
GO:0005515 protein binding	IPI PMID:37398436 AI-guided pipeline for protein-protein interaction drug disc...	MARK AS OVER ANNOTATED	Summary: AI-guided PPI drug-discovery pipeline recording a FANCA-FANCG interaction. High-throughput/computational-plus-experimental protein binding. Reason: Generic protein binding term; uninformative for molecular function.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Multimodal cell-maps interactome study; recorded FANCA partner is FANCG. High-throughput protein binding. Reason: High-throughput interactome data annotated as generic protein binding; uninformative MF term.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence (Human Protein Atlas) localizes FANCA to the nucleoplasm, consistent with the nuclear site of action of the FA core complex. Reason: Direct immunofluorescence evidence for nucleoplasmic localization; consistent with the functional nuclear compartment of FANCA.
GO:0000785 chromatin	IDA PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr...	ACCEPT	Summary: FANCA undergoes DNA-damage-induced chromatin loading (dependent on the FAAP20 UBZ domain), placing it at chromatin where crosslink repair is initiated. Reason: Direct evidence that FANCA is loaded onto chromatin after DNA damage; a functionally relevant location for the FA core complex. Supporting Evidence: PMID:22343915 but is required for DNA-damage-induced chromatin loading of FANCA and the
GO:0036297 interstrand cross-link repair	NAS PMID:19965384 The Fanconi anemia pathway promotes replication-dependent DN...	ACCEPT	Summary: The FA pathway (of which FANCA is a core-complex subunit) promotes replication-dependent repair of DNA interstrand crosslinks via monoubiquitination of FANCI-FANCD2. Core biological process. Reason: Well-supported core process for FANCA. Consistent with the IEA ICL-repair annotation and the broader DNA-repair role. Supporting Evidence: PMID:19965384 hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs)
GO:0043240 Fanconi anaemia nuclear complex	NAS PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr...	ACCEPT	Summary: FAAP20 study confirming FANCA as an integral component of the FA nuclear core complex, with a defined FANCA region binding FAAP20. Reason: Directly supports FANCA membership in the FA nuclear complex; core CC annotation. Supporting Evidence: PMID:22343915 that FAAP20 is an integral component of the FA nuclear core complex. We identify
GO:0005829 cytosol	TAS Reactome:R-HSA-9835411	KEEP AS NON CORE	Summary: Reactome places FANCA (in a core-complex:HSP70 assembly binding PKR) in the cytosol. This reflects a cytoplasmic/pre-assembly pool rather than the functional nuclear site. Reason: Cytosolic localization is consistent with the known minor cytoplasmic pool of FANCA, but the core DNA-repair function occurs in the nucleus; keep as non-core.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785126	ACCEPT	Summary: Reactome (FA core complex assembles at ICLs) localizes FANCA to the nucleoplasm, the functional compartment of the FA pathway. Reason: Consistent with the nucleoplasmic site of FA core-complex action; supported by IDA localization evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785342	ACCEPT	Summary: Reactome nucleoplasm annotation for FANCA within the FA/ICL-repair reaction set. Reason: Correct functional location; consistent with other nucleoplasm evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785361	ACCEPT	Summary: Reactome nucleoplasm annotation for FANCA within the FANCD2:FANCI monoubiquitination reaction context. Reason: Correct functional location; consistent with other nucleoplasm evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785732	ACCEPT	Summary: Reactome nucleoplasm annotation for FANCA in the ICL-repair reaction set. Reason: Correct functional location; consistent with other nucleoplasm evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785986	ACCEPT	Summary: Reactome nucleoplasm annotation for FANCA in the ICL-unhooking reaction set. Reason: Correct functional location; consistent with other nucleoplasm evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6786155	ACCEPT	Summary: Reactome nucleoplasm annotation for FANCA in the ICL-repair reaction set. Reason: Correct functional location; consistent with other nucleoplasm evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6786166	ACCEPT	Summary: Reactome nucleoplasm annotation for FANCA in the translesion-synthesis reaction context. Reason: Correct functional location; consistent with other nucleoplasm evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6786171	ACCEPT	Summary: Reactome nucleoplasm annotation for FANCA in the FANCD2-deubiquitination reaction context. Reason: Correct functional location; consistent with other nucleoplasm evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6788385	ACCEPT	Summary: Reactome nucleoplasm annotation for FANCA in the ATR/ATRIP recruitment reaction context. Reason: Correct functional location; consistent with other nucleoplasm evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6788392	ACCEPT	Summary: Reactome nucleoplasm annotation for FANCA in the ATR-phosphorylation reaction context. Reason: Correct functional location; consistent with other nucleoplasm evidence.
GO:0005515 protein binding	IPI PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr...	MARK AS OVER ANNOTATED	Summary: Direct interaction between FANCA and FAAP20/C1orf86; FANCA regulates FAAP20 stability. Direct and functionally important, annotated as generic protein binding. Reason: The FANCA-FAAP20 interaction is direct and central to core-complex integrity, but GO:0005515 is uninformative. Captured in core_functions. Supporting Evidence: PMID:22343915 a region on FANCA that physically interacts with FAAP20, and show that FANCA
GO:0005515 protein binding	IPI PMID:22705371 A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubi...	MARK AS OVER ANNOTATED	Summary: FAAP20 (a component of the FA core complex, bound by FANCA) links RNF8-mediated ubiquitination to the FA network. Annotated as generic protein binding. Reason: Real, functionally important core-complex interaction, but GO:0005515 is uninformative for molecular function. Supporting Evidence: PMID:22705371 by RNF8 and its partner, UBC13, and mediated by FAAP20, a component of the FA
GO:0043240 Fanconi anaemia nuclear complex	IDA PMID:22266823 Regulation of Rev1 by the Fanconi anemia core complex.	ACCEPT	Summary: Direct identification of FANCA within the multisubunit FA core complex (Rev1-regulation study identifying FAAP20 as an integral subunit binding FANCA). Reason: Direct experimental evidence for FANCA membership in the FA core complex; core CC annotation. Supporting Evidence: PMID:22266823 multisubunit Fanconi anemia core complex. FAAP20 binds to FANCA subunit and is
GO:0043240 Fanconi anaemia nuclear complex	IDA PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr...	ACCEPT	Summary: Direct evidence that FANCA is an integral component of the FA nuclear core complex (FAAP20 study). Reason: Direct experimental support for the core CC annotation. Supporting Evidence: PMID:22343915 that FAAP20 is an integral component of the FA nuclear core complex. We identify
GO:0043240 Fanconi anaemia nuclear complex	IDA PMID:22705371 A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubi...	ACCEPT	Summary: FANCA identified as part of the FA core complex whose recruitment to ICLs is regulated by the RNF8-FAAP20 ubiquitin cascade. Reason: Direct experimental support for FANCA membership in the FA nuclear complex.
GO:0043240 Fanconi anaemia nuclear complex	IDA PMID:20347428 A histone-fold complex and FANCM form a conserved DNA-remode...	ACCEPT	Summary: FANCM-MHF histone-fold complex study in which FANCA is identified as part of the FA core complex. Reason: Direct experimental support for the core CC annotation; consistent with all other complex-membership evidence.
GO:0005515 protein binding	IPI PMID:11726552 Fanconi anemia protein, FANCA, associates with BRG1, a compo...	MARK AS OVER ANNOTATED	Summary: FANCA associates with BRG1/SMARCA4 (a subunit of the SWI/SNF chromatin-remodeling complex) and co-localizes with it in the nucleus. Real interaction, uninformative MF term; a proposed link to chromatin remodeling/transcription. Reason: GO:0005515 protein binding is uninformative. The FANCA-BRG1/SWI-SNF interaction is a plausible but secondary/peripheral activity relative to the core FA-complex DNA-repair function. Supporting Evidence: PMID:11726552 FANCA was demonstrated to associate with the endogenous SWI/SNF
GO:0005634 nucleus	IDA PMID:11726552 Fanconi anemia protein, FANCA, associates with BRG1, a compo...	ACCEPT	Summary: Direct evidence of nuclear localization of FANCA (co-localization with BRG1 in the nucleus). Reason: Direct experimental support for the functional nuclear localization of FANCA. Supporting Evidence: PMID:11726552 between transfected FANCA and BRG1
GO:0005515 protein binding	IPI PMID:12571280 Nonerythroid alphaII spectrin is required for recruitment of...	MARK AS OVER ANNOTATED	Summary: FANCA co-immunoprecipitates with nonerythroid alphaII-spectrin and ERCC4/XPF and is recruited to ICL-induced nuclear foci. Real interaction relevant to ICL repair, but annotated as generic protein binding. Reason: The FANCA-spectrin-XPF interactions are functionally relevant to recruitment at crosslink damage, but GO:0005515 is uninformative for molecular function. Supporting Evidence: PMID:12571280 alphaSpIISigma*, FANCA and XPF co-immunoprecipitate with each other from normal
GO:0005634 nucleus	TAS PMID:9398857 The Fanconi anaemia proteins, FAA and FAC, interact to form ...	ACCEPT	Summary: The FAA-FAC (FANCA-FANCC) complex is found in the nucleus (as well as cytoplasm); nuclear localization is essential for FA-pathway function. Reason: Supports the functional nuclear localization of FANCA; consistent with IEA/IDA nucleus evidence. Supporting Evidence: PMID:9398857 is found in similar abundance in both cytoplasm and nucleus
GO:0005737 cytoplasm	TAS PMID:9398857 The Fanconi anaemia proteins, FAA and FAC, interact to form ...	KEEP AS NON CORE	Summary: Unbound FANCA/FANCC localize predominantly to the cytoplasm; a minor cytoplasmic pool exists. Non-core (pre-assembly/inactive) location. Reason: Cytoplasmic localization is documented but does not represent the functional nuclear site of FANCA action; keep as non-core, consistent with the IEA cytoplasm annotation. Supporting Evidence: PMID:9398857 unbound FAA and FAC localize predominantly to the cytoplasm, the FAA-FAC complex
GO:0006281 DNA repair	TAS PMID:8896564 Positional cloning of the Fanconi anaemia group A gene.	ACCEPT	Summary: FANCA was cloned as an FA group A gene and proposed to belong to a class of genes associated with prevention/repair of DNA damage. Correct, broader parent of the more specific interstrand cross-link repair. Reason: DNA repair is an accurate (if general) biological-process annotation for FANCA; it is broader than but consistent with the ICL-repair annotation, and it is acceptable to retain the parent term. Supporting Evidence: PMID:8896564 new class of genes associated with the prevention or repair of DNA damage
GO:0065003 protein-containing complex assembly	TAS PMID:9398857 The Fanconi anaemia proteins, FAA and FAC, interact to form ...	ACCEPT	Summary: FANCA is required for formation and stability of the FA core complex (it binds FANCG/FANCF, anchors and stabilizes FAAP20, and the FAA-FAC complex forms only in functional cells). Assembly of the multiprotein complex is a genuine role. Reason: FANCA participates directly in assembly of the FA core complex; supported by demonstration that FANCA and FANCC bind each other and form a complex, and by FANCA-dependent stability of core-complex partners. Supporting Evidence: PMID:9398857 the FAA and FAC bind each other and form a complex
GO:0030674 protein-macromolecule adaptor activity	IPI PMID:22266823 Regulation of Rev1 by the Fanconi anemia core complex.	NEW	Summary: Proposed informative molecular-function annotation replacing the uninformative protein binding calls. FANCA acts as a scaffold/adaptor that brings together core-complex subunits (binds FANCG/FANCF and directly anchors FAAP20), coordinating assembly and function of the FA core complex. Reason: FANCA is a non-catalytic scaffolding subunit whose defining biochemical activity is bridging protein partners within the FA core complex; the many FANCA IPI annotations to generic protein binding (e.g. FANCG, FANCF, FAAP20) are better represented by an adaptor activity. FAAP20 binds directly to the FANCA subunit and FANCA is required for complex stability. Supporting Evidence: PMID:22266823 multisubunit Fanconi anemia core complex. FAAP20 binds to FANCA subunit and is PMID:22343915 a region on FANCA that physically interacts with FAAP20, and show that FANCA
GO:0003697 single-stranded DNA binding	IDA PMID:22194614 Fanconi anemia complementation group A (FANCA) protein has i...	NEW	Summary: Purified FANCA has an intrinsic nucleic-acid-binding activity with preference for single-stranded over double-stranded DNA (and RNA > ssDNA > dsDNA), mapped to its C-terminal domain where most disease mutations cluster. This activity is absent from the curated GOA set; it is added here as a well-documented but single-lab intrinsic activity surfaced by the Affinage record. Reason: Two primary papers from one group (Zhang lab) show purified FANCA directly binds ssDNA by EMSA, with a patient-derived truncation (Q772X) deficient and the C-terminal fragment C772-1455 retaining binding. This intrinsic ssDNA-binding activity is proposed to help recruit and assemble the FA core complex at stalled replication forks. It is a real biochemical activity but has not been independently replicated or adopted by GO curators, so it is treated as a non-core molecular function. Supporting Evidence: PMID:22194614 Using purified protein, we report that human FANCA has intrinsic affinity for nucleic acids. PMID:22194614 its affinity for ssDNA is significantly higher than for dsDNA in an electrophoretic mobility shift assay
GO:0045002 double-strand break repair via single-strand annealing	IMP PMID:30057198 FANCA Promotes DNA Double-Strand Break Repair by Catalyzing ...	NEW	Summary: Beyond its canonical core-complex scaffold role, purified FANCA catalyzes single-strand annealing and strand exchange comparable to RAD52, and cell-based DSB-repair assays (siRNA knockdown, CRISPR knockout, mutant complementation) show FANCA is specifically required for the single-strand-annealing sub-pathway of DSB repair, independently of the canonical FA pathway and RAD52. Not present in the curated GOA set. Reason: PMID:30057198 (Mol Cell) demonstrates FANCA SA/SE activity in vitro (with a homodimerization requirement, and six patient-derived mutants deficient) and a direct cellular role in the SSA sub-pathway of DSB repair that is distinct from FANCD2 monoubiquitination. GO:0045002 is a real, correctly-branched biological-process term. This is a well-documented but single-lab, non-canonical activity absent from the curated annotations; added as non-core. Supporting Evidence: PMID:30057198 The SA and SE activities of FANCA directly explain its role in homology-directed DSB repair. PMID:30057198 Our cell-based DSB repair assay further demonstrates that FANCA contributes to the repair of DNA double strand breaks independently of the FA pathway and RAD52 in human cells.

Core Functions

As an essential, non-catalytic structural subunit and protein-interaction hub of the multiprotein Fanconi anemia (FA) core complex, FANCA acts as a scaffold/adaptor that binds FANCG and FANCF and directly anchors FAAP20, promoting assembly, stability, nuclear accumulation and chromatin loading of the core complex so that it can monoubiquitinate the FANCD2-FANCI complex during replication-coupled repair of DNA interstrand crosslinks.

Molecular Function:

protein-macromolecule adaptor activity

Directly Involved In:

interstrand cross-link repair protein-containing complex assembly

Cellular Locations:

nucleoplasm chromatin

In Complex:

Fanconi anaemia nuclear complex

Supporting Evidence:

PMID:22266823
multisubunit Fanconi anemia core complex. FAAP20 binds to FANCA subunit and is
PMID:22343915
a region on FANCA that physically interacts with FAAP20, and show that FANCA

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

PMID:10627486

Strong FANCA/FANCG but weak FANCA/FANCC interaction in the yeast 2-hybrid system.

PMID:10652215

Investigation of Fanconi anemia protein interactions by yeast two-hybrid analysis.

PMID:11063725

The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG.

PMID:11726552

Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex.

PMID:12571280

Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links.

PMID:12649160

Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:17289582

Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.

PMID:17396147

FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway.

PMID:17474147

Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening.

PMID:19965384

The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.

PMID:20347428

A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability.

PMID:22266823

Regulation of Rev1 by the Fanconi anemia core complex.

PMID:22343915

FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required for functional integrity of the FA-BRCA DNA repair pathway.

PMID:22705371

A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network.

PMID:22194614

Fanconi anemia complementation group A (FANCA) protein has intrinsic affinity for nucleic acids with preference for single-stranded forms.

PMID:30057198

FANCA Promotes DNA Double-Strand Break Repair by Catalyzing Single-Strand Annealing and Strand Exchange.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:37398436

AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:8896564

Positional cloning of the Fanconi anaemia group A gene.

PMID:9398857

The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex.

Reactome:R-HSA-6785126

FA core complex assembles at DNA interstrand crosslinks (ICLs)

Reactome:R-HSA-6785342

FANCD2:FANCI complex and UBE2T bind ICL-DNA associated with the FA core complex

Reactome:R-HSA-6785361

Monoubiquitination of FANCD2:FANCI

Reactome:R-HSA-6785732

DNA nucleases bind monoubiquitinated ID2 complex

Reactome:R-HSA-6785986

DNA nucleases unhook the interstrand crosslink (ICL)

Reactome:R-HSA-6786155

POLN binds ICL-DNA

Reactome:R-HSA-6786166

Translesion synthesis across unhooked ICL by POLN

Reactome:R-HSA-6786171

FANCD2 deubiquitination by USP1:WDR48

Reactome:R-HSA-6788385

The complex of ATR and ATRIP is recruited to ICL-DNA

Reactome:R-HSA-6788392

ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA

Reactome:R-HSA-9835411

FA core complex:HSP70s binds PKR

Deep Research

Affinage

(FANCA-deep-research-affinage.md)

Affinage mechanistic annotation for FANCA (human) Affinage Affinage (Claude Sonnet reading pass + Opus synthesis pass) 29 citations

Affinage mechanistic annotation for FANCA (human)

Current model (mechanistic narrative)

FANCA is a large nuclear protein that serves as a scaffold organizer of the Fanconi anemia (FA) core complex, the assembly required for activating the FA/BRCA interstrand crosslink (ICL) repair pathway [PMID:9789045, PMID:21273304]. Through an N-terminal arginine-rich motif (residues 18–29, with Arg1/Arg2/Leu8 critical) FANCA binds FANCG, and the two proteins reciprocally stabilize each other and promote nuclear accumulation of the complex [PMID:10567393, PMID:11050007, PMID:32002546]; cryo-EM defines a C-terminal arc-shaped HEAT-repeat solenoid that forms a pseudo-symmetric dimer and engages FANCG at both N- and C-terminal interfaces, with disease mutations at these contacts blocking nuclear import and pathway function PMID:32002546. FANCA additionally complexes with FANCC and FANCF, and its nuclear localization is necessary and sufficient for correcting mitomycin C hypersensitivity in FA-A cells, distinct from FANCC's separable cytoplasmic role [PMID:9398857, PMID:9746759, PMID:11063725]. FAAP20 directly binds and stabilizes FANCA, and its loss reduces FANCD2 monoubiquitination and reproduces FA phenotypes, placing FANCA upstream of the central ICL-repair switch PMID:22396592. Patient-derived missense and truncation mutations cause FA by preventing nuclear relocation and pathway activation rather than by graded loss of an intrinsic activity, accounting for the absence of genotype–phenotype correlation PMID:21273304. FANCA is regulated by DNA-damage-induced ATR phosphorylation on Ser1449 and by NEK2 phosphorylation on Thr351 at centrosomes [PMID:19109555, PMID:23806870]. Beyond core-complex scaffolding, purified FANCA possesses intrinsic nucleic acid binding (RNA > ssDNA > dsDNA) via its C-terminal domain and directly catalyzes single-strand annealing and strand exchange comparable to RAD52, acting in the single-strand-annealing branch of double-strand break repair independently of the canonical FA pathway, with FANCG stimulating these activities [PMID:22194614, PMID:30057198]. FANCA also localizes to centrosomes and pericentriolar material during mitosis, where it maintains centrosomal integrity, spindle assembly, and spindle-assembly-checkpoint function [PMID:23806870, PMID:26366677]. It engages additional partners — BRCA1, the SWI/SNF subunit BRG1, alpha-spectrin II, and mu-calpain — linking it to chromatin and to a spectrin scaffold that recruits FANCA to crosslink sites [PMID:10551855, PMID:11726552, PMID:12354784, PMID:20518497].

Affinage mechanism profile (Affinage's own GO/Reactome grounding)

molecular_activity: GO:0003677 DNA binding, GO:0003723 RNA binding, GO:0140097 catalytic activity, acting on DNA, GO:0060090 molecular adaptor activity, GO:0005198 structural molecule activity
localization: GO:0005634 nucleus, GO:0005829 cytosol, GO:0005815 microtubule organizing center
pathway (Reactome): R-HSA-73894 DNA Repair, R-HSA-1640170 Cell Cycle
partners: FANCG, FANCC, FANCF, FAAP20, BRCA1, BRG1, SPTAN1, NEK2
complexes: Fanconi anemia core complex

Dated findings (citation-anchored)

Year	Confidence	Finding	PMIDs	Journal
1996	Medium	FANCA (FAA) encodes a predicted 162,752 Da protein containing two overlapping bipartite nuclear localization signals and a partial leucine zipper consensus, suggestive of nuclear localization and function.	PMID:8896563	Nature genetics
1997	High	FANCA (FAA) and FANCC (FAC) proteins bind each other to form a complex; the complex localizes to both cytoplasm and nucleus, whereas unbound FAA and FAC localize predominantly to the cytoplasm.	PMID:9398857	Nature genetics
1998	High	Nuclear localization of FANCA is necessary but not sufficient for its functional activity; FANCA requires binding to FANCC for complementation activity, and mutant FANCA that cannot bind FANCC fails to promote nuclear accumulation of FANCC and is non-functional.	PMID:9742112	Molecular and cellular biology
1998	High	FANCA is phosphorylated in normal lymphoblasts; this phosphorylation, together with FANCA/FANCC complex formation and nuclear accumulation of the complex, is defective in FA cells from multiple complementation groups (A, B, C, E, F, G, H), defining these events as part of a shared FA signaling pathway.	PMID:9789045	Proceedings of the National Academy of Sciences of the United States of America
1999	High	FANCA and FANCG form a physical complex both in vivo and in vitro; this complex is detected in non-FA cells and FA-D and FA-E cells, but absent in FA-A and FA-G cells; disruption of the complex correlates with the FA cellular phenotype.	PMID:10468606	Proceedings of the National Academy of Sciences of the United States of America
1999	High	FANCA, FANCC, and FANCG interact in a functional nuclear complex; the amino-terminal region of FANCA is required for FANCG binding, FANCC binding, nuclear localization, and functional activity of the complex.	PMID:10373536	Molecular and cellular biology
1999	High	Nuclear localization of FANCA is necessary and sufficient to correct mitomycin C sensitivity in FA-A cells; FANCA with nuclear export signal failed to correct, while FANCA with nuclear localization signal corrected. Separate from FANCC function in the cytoplasm.	PMID:9746759	Blood
1999	Medium	Alpha spectrin II (alphaSpIISigma) forms a nuclear complex with FANCA and FANCC; levels of alphaSpIISigma are significantly reduced in FA-A, FA-B, FA-C, and FA-D cells, suggesting FA proteins are required for stability or expression of alphaSpIISigma*.	PMID:10551855	The Journal of biological chemistry
1999	High	A patient-derived FANCA mutation (H1110P) abolishes FANCA phosphorylation, FANCC binding, nuclear accumulation, and functional complementation of MMC sensitivity.	PMID:10210316	Experimental hematology
1999	High	FANCA interaction domain for FANCG maps to amino acids 18–29 of FANCA (arginine-rich motif RRRAWAELLAG); alanine mutagenesis identified Arg1, Arg2, and Leu8 as critical residues. FANCA-FANCG complex formation and nuclear co-localization are required for cellular resistance to MMC.	PMID:10567393	The Journal of biological chemistry
2000	High	FANCG binds directly to the amino-terminal NLS region of FANCA, stabilizes FANCA protein by prolonging its cellular half-life, and promotes nuclear accumulation of the FA protein complex; the reciprocal is also true (FANCA stabilizes FANCG). Carboxy-terminal leucine zipper mutations in FANCA allow cytoplasmic FANCG binding but block nuclear translocation.	PMID:11050007	Blood
2000	High	FANCF forms a nuclear complex with FANCA, FANCC, and FANCG; each FA protein except FANCD is required for these complexes to form.	PMID:11063725	Human molecular genetics
2001	Medium	FANCA protein associates with BRG1, a component of the human SWI/SNF chromatin-remodeling complex; FANCA co-localizes with BRG1 in the nucleus and co-purifies with the endogenous SWI/SNF complex.	PMID:11726552	Human molecular genetics
2001	Medium	AlphaSpIISigma, FANCA, FANCC, and FANCG proteins specifically bind to DNA containing psoralen interstrand cross-links; purified brain spectrin directly binds cross-linked DNA, suggesting alphaSpIISigma scaffolds FA proteins at damage sites.	PMID:11401546	Biochemistry
2001	Medium	A cytoplasmic serine protein kinase (FANCA-PK), sensitive to wortmannin, forms a complex with FANCA and phosphorylates it; this kinase is also present in the FANCA/FANCG complex, suggesting it is a regulatory component of the FA complex.	PMID:11739169	Blood
2002	High	BRCA1 directly interacts with FANCA; the interaction involves the amino-terminal portion of FANCA and the central part (aa 740–1083) of BRCA1; the interaction is constitutive and does not require DNA damage.	PMID:12354784	Human molecular genetics
2003	Medium	AlphaSpIISigma is essential for DNA-damage-induced recruitment of FANCA and XPF to nuclear foci following treatment with psoralen/UVA; FA-A cells with decreased alphaSpIISigma show reduced XPF and alphaSpIISigma focus formation; correction with FANCA cDNA restores alphaSpIISigma levels and nuclear focus formation.	PMID:12571280	Journal of cell science
2008	High	ATR phosphorylates FANCA on serine 1449 in response to DNA damage (not during S phase); ATR-dependent phosphorylation is confirmed both in vivo (ATR-deficient cells lack it) and in vitro (ATR kinase directly phosphorylates FANCA-S1449); the S1449A phospho-deficient mutant fails to fully complement FA-associated phenotypes.	PMID:19109555	Blood
2011	High	Purified FANCA protein has intrinsic nucleic acid-binding activity, preferring ssDNA > dsDNA, with RNA binding even stronger; minimum ~30 nucleotides required; a 5'-flap or 5'-tail facilitates binding; the nucleic acid-binding domain localizes primarily to the C-terminus. A patient-derived truncation mutant (Q772X) shows diminished binding, while the C-terminal fragment C772-1455 retains binding activity.	PMID:22194614	The Journal of biological chemistry
2012	High	FAAP20 is a component of the FA core complex that directly interacts with FANCA and stabilizes it; loss of FAAP20 reduces FANCD2 monoubiquitination and causes hallmarks of FA (MMC hypersensitivity, chromosome aberrations).	PMID:22396592	Proceedings of the National Academy of Sciences of the United States of America
2013	High	FANCA co-immunoprecipitates with NEK2 kinase and localizes to centrosomes (notably during mitosis); NEK2 phosphorylates FANCA at threonine-351 in vitro; the phosphorylation-defective T351A mutant shows centrosomal abnormalities, aberrant mitotic arrest, and enhanced nocodazole sensitivity; FANCA knockdown increases centrosomal abnormality frequency.	PMID:23806870	The international journal of biochemistry & cell biology
2014	Medium	FANCA modulates neddylation of the chemokine receptor CXCR5; FANCA (but not FANCC) is required for CXCR5 neddylation, which promotes CXCR5 membrane targeting and cell migration/motility.	PMID:25015289	Journal of cell science
2014	Medium	Fanca is required for transition mutations at A/T residues during somatic hypermutation in B cells, and for stabilizing short microhomology duplexes during class switch recombination, thereby impeding short-range recombination downstream of double-strand breaks.	PMID:24799500	The Journal of experimental medicine
2015	Medium	FANCA shuttles to the pericentriolar material to regulate spindle assembly at mitotic entry; loss of FA signaling renders cells hypersensitive to spindle chemotherapeutics and allows escape from the spindle assembly checkpoint.	PMID:26366677	Experimental hematology
2018	High	Purified FANCA protein catalyzes bidirectional single-strand annealing (SA) and strand exchange (SE) at levels comparable to RAD52; FANCG directly interacts with FANCA and stimulates its SA and SE activities; a disease-causing mutant (F1263Δ) and five other patient-derived mutants are deficient in SA and SE; FANCA plays a direct role in the SSA sub-pathway of DSB repair independently of the canonical FA pathway and RAD52.	PMID:30057198	Molecular cell
2020	High	The cryo-EM structure of Xenopus FANCA alone (3.35/3.46 Å) reveals a C-terminal domain (CTD) with an arc-shaped solenoid structure forming a pseudo-symmetric dimer; two cryo-EM structures of FANCA-FANCG complex (4.59/4.84 Å) show FANCG independently contacts either the FANCA C-terminal HEAT repeats or the N-terminal region; mutations disrupting either interaction prevent FANCA nuclear localization and FA pathway function.	PMID:32002546	Nucleic acids research
2010	Medium	Cytoplasmic FANCA and FANCC form a cytoplasmic subcomplex that interacts with and stabilizes the leukemic nucleophosmin NPMc; loss of FANCA or FANCC leads to NPMc ubiquitination by IBRDC2 and proteasomal degradation; depletion of FANCA and FANCC in NPMc-positive leukemic cells increases NF-κB activation.	PMID:20864535	The Journal of biological chemistry
2010	Medium	FANCA and FANCG bind directly to mu-calpain; this binding may inhibit mu-calpain activity in normal cells, thereby maintaining stability of alphaIISp; in FA-A cells, increased mu-calpain activity leads to increased alphaIISp breakdown, and siRNA knockdown of mu-calpain in FA-A cells restores alphaIISp levels and corrects DNA interstrand cross-link repair defects and chromosomal instability.	PMID:20518497	Biochemistry
2011	Medium	Missense mutations in FANCA that cause FA lead to altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway, explaining the lack of correlation between FANCA mutation type and cellular or clinical phenotype severity.	PMID:21273304	Blood

Citations

PMID:10210316
PMID:10373536
PMID:10468606
PMID:10551855
PMID:10567393
PMID:11050007
PMID:11063725
PMID:11401546
PMID:11726552
PMID:11739169
PMID:12354784
PMID:12571280
PMID:19109555
PMID:20518497
PMID:20864535
PMID:21273304
PMID:22194614
PMID:22396592
PMID:23806870
PMID:24799500
PMID:25015289
PMID:26366677
PMID:30057198
PMID:32002546
PMID:8896563
PMID:9398857
PMID:9742112
PMID:9746759
PMID:9789045

📚 Additional Documentation

Notes

(FANCA-notes.md)

FANCA (human) — gene review notes

UniProt: O15360 (FANCA_HUMAN), 1455 aa. Gene on 16q24.3. Synonyms FAA, FACA, FANCH.
Accounts for ~60-65% of Fanconi anemia cases.

Summary of function

FANCA is one of the eight Fanconi anemia (FA) proteins (FANCA, B, C, E, F, G,
L/PHF9, M) that assemble into the multisubunit FA core complex (FA nuclear
complex; GO:0043240; ComplexPortal CPX-6263 "Fanconi anemia ubiquitin ligase
complex"). The core complex is a nuclear E3 ubiquitin-ligase assembly (catalytic
RING subunit = FANCL, E2 = UBE2T/FANCT) that, in response to DNA interstrand
crosslinks (ICLs) encountered during replication, monoubiquitinates the
FANCD2-FANCI (ID2) heterodimer. Monoubiquitinated ID2 is loaded onto chromatin
and coordinates downstream nucleolytic incision, translesion synthesis (TLS), and
homologous-recombination repair. FANCA itself is not the catalytic subunit; it is
a large scaffolding/docking subunit and the principal protein-protein interaction
hub of the core complex.

Key provenance

Positional cloning / identity

PMID:8896564

Nuclear complex membership (GO:0043240)

PMID:9398857 and
PMID:9398857
PMID:11063725
PMID:12649160
PMID:22343915
PMID:22266823
UniProt SUBUNIT: "Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM."

Interstrand cross-link repair (GO:0036297) / DNA repair (GO:0006281)

PMID:19965384 — FANCA is a core-complex subunit required for this activation.
PMID:22266823 and
PMID:22266823

Subcellular location

Nucleus (major functional form) and cytoplasm (minor form):
UniProt SUBCELLULAR LOCATION "Nucleus. Cytoplasm. Note=The major form is nuclear. The minor form is cytoplasmic."
PMID:9398857
Nuclear localization + phosphorylation required for function (UniProt refs PMID:9742112, PMID:9789045; NLS motif 18-34).
Chromatin loading is DNA-damage-induced: PMID:22343915

Protein interactions (all GO:0005515 protein binding — uninformative MF; scaffold/hub role)

FANCA is the central interaction hub of the core complex. Verified partners in cached lit:
- FANCG (O15287): PMID:10627486;
PMID:10652215;
PMID:12649160
- FANCF (Q9NPI8): PMID:11063725
- FAAP24 (via FANCM), FAAP100 (Q0VG06): PMID:17396147; PMID:17289582 FAAP24 targets FANCM.
- FAAP20/C1orf86 (Q6NZ36): PMID:22343915, PMID:22705371, PMID:22266823
- SMARCA4/BRG1 (P51532), SWI/SNF: PMID:11726552; PMID:11726552
- ERCC4/XPF (Q92889) + nonerythroid αII-spectrin: PMID:12571280
- GRB2 (P62993): SH3 peptide-array screen PMID:17474147 — high-throughput, peripheral.
- Large-scale interactome / proteomics screens (FANCG or FAAP100 baits): PMID:16189514, PMID:28514442, PMID:32814053, PMID:33961781, PMID:35271311, PMID:37398436, PMID:40205054 — high-throughput, uninformative.

regulation of regulatory T cell differentiation (GO:0045589, IBA)

Phylogenetic (PANTHER/GO_Central) inference seeded from mouse Fanca (MGI:1341823).
Peripheral/pleiotropic; not a core molecular function of the DNA-repair scaffold.
Treat as non-core.

protein-containing complex assembly (GO:0065003, TAS PMID:9398857)

FANCA is required for formation/stability of the FA core complex (binds FANCG/FANCF/FAAP20;
regulates FAAP20 stability). Genuine but essentially a restatement of complex membership.

Structure

Cryo-EM structures of the human FA core complex: PDB 7KZP/7KZQ/7KZR/7KZS/7KZT/7KZV
(1-1455). FANCA is largely α-helical (Pfam FANCA_arcN, FANCA_helical, FANCA_CTD, Fanconi_A_N).

Action plan for annotations

GO:0043240 FA nuclear complex (IBA/IEA/NAS/IDA x7): ACCEPT (core; must be consistent).
GO:0005515 protein binding (all IPI): MARK_AS_OVER_ANNOTATED (uninformative; hub role captured in core_functions/notes).
GO:0036297 ICL repair (IEA/NAS): ACCEPT (core BP).
GO:0006281 DNA repair (TAS): ACCEPT (correct broader BP).
GO:0005634 nucleus (IEA/IDA/TAS): ACCEPT (functional location).
GO:0005654 nucleoplasm (IDA/TAS x10): ACCEPT.
GO:0000785 chromatin (IDA): ACCEPT (DNA-damage-induced loading).
GO:0005737 cytoplasm (IEA/TAS): KEEP_AS_NON_CORE (minor/inactive form).
GO:0005829 cytosol (TAS): KEEP_AS_NON_CORE.
GO:0065003 complex assembly (TAS): ACCEPT.
GO:0045589 Treg differentiation (IBA): KEEP_AS_NON_CORE (pleiotropic, mouse-ortholog-derived).

📄 View Raw YAML

id: O15360
gene_symbol: FANCA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: FANCA is one of the Fanconi anemia (FA) proteins and an essential structural
  subunit of the multiprotein FA core complex (also called the Fanconi anaemia nuclear
  complex), which is composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9
  and FANCM together with associated FAAP proteins (FAAP20, FAAP24, FAAP100). The FA
  core complex is a nuclear multisubunit E3 ubiquitin ligase (with FANCL as the catalytic
  RING subunit and UBE2T/FANCT as the E2) that, in response to DNA interstrand crosslinks
  encountered during replication, monoubiquitinates the FANCD2-FANCI (ID2) heterodimer.
  Monoubiquitinated ID2 is loaded onto chromatin and coordinates downstream nucleolytic
  incision, translesion synthesis and homologous-recombination repair of the crosslink.
  FANCA is not the catalytic subunit; it is a large, predominantly alpha-helical scaffolding
  and protein-interaction hub that binds FANCG and FANCF and directly anchors FAAP20,
  and it is required for the assembly, stability, nuclear accumulation and chromatin
  loading of the core complex. The functional form of FANCA is nuclear (a minor pool
  is cytoplasmic), and its nuclear accumulation depends on FANCC binding and phosphorylation.
  Biallelic loss-of-function mutations in FANCA are the most common cause of Fanconi
  anemia (complementation group A, ~60-65% of cases), a chromosomal-instability syndrome
  with bone-marrow failure, congenital malformations, cellular hypersensitivity to DNA
  crosslinking agents, and cancer predisposition.
alternative_products:
- name: '1'
  id: O15360-1
- name: '2'
  id: O15360-2
  sequence_note: VSP_007039
- name: '3'
  id: O15360-3
  sequence_note: VSP_054682
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: FANCA is a core structural subunit of the multiprotein FA nuclear (core)
      complex. This is the central, well-established cellular-component annotation for
      FANCA and is supported phylogenetically, electronically, and by multiple experimental
      studies.
    action: ACCEPT
    reason: FANCA is definitively a component of the FA core complex (FANCA/B/C/E/F/G/L/M
      plus FAAP proteins), which monoubiquitinates FANCD2-FANCI. The IBA call is consistent
      with direct experimental evidence.
    supported_by:
    - reference_id: PMID:12649160
      supporting_text: proteins form a nuclear complex required for the monoubiquination
        of the
- term:
    id: GO:0045589
    label: regulation of regulatory T cell differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (PANTHER/GO_Central) inference seeded from a mouse Fanca annotation
      (MGI:1341823). This reflects a peripheral/pleiotropic immunological role rather
      than the core DNA-repair scaffolding function of FANCA.
    action: KEEP_AS_NON_CORE
    reason: FA proteins have been implicated in immune phenotypes in mouse models, so
      this is not clearly wrong, but regulation of regulatory T cell differentiation
      is not a core molecular activity of a DNA interstrand-crosslink-repair core-complex
      subunit. It is a context-specific, non-core process derived from a single ortholog
      annotation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: FANCA localizes to the nucleus, which is the compartment where the functional
      FA core complex acts. Electronic mapping from the UniProt subcellular-location
      vocabulary is consistent with experimental data.
    action: ACCEPT
    reason: The major, functional form of FANCA is nuclear (UniProt SUBCELLULAR LOCATION;
      the FAA-FAC complex is found in the nucleus). Correct location annotation.
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: is found in similar abundance in both cytoplasm and nucleus
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: A minor pool of FANCA is cytoplasmic; unbound FANCA/FANCC localize predominantly
      to the cytoplasm before assembly/nuclear import. This represents a non-core (inactive/pre-assembly)
      location rather than the functional nuclear site of action.
    action: KEEP_AS_NON_CORE
    reason: UniProt notes the major form is nuclear and the minor form cytoplasmic. Cytoplasmic
      localization is real but is not where FANCA performs its DNA-repair function; keep
      as non-core.
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: unbound FAA and FAC localize predominantly to the cytoplasm, the
        FAA-FAC complex
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: FANCA is a core-complex subunit essential for the FA pathway that repairs
      DNA interstrand crosslinks via monoubiquitination of FANCD2-FANCI. This is a core
      biological process for FANCA.
    action: ACCEPT
    reason: InterPro2GO mapping (IPR003516, FANCA family) to interstrand cross-link repair
      is biologically accurate and matches experimental and pathway knowledge.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: central event in the activation of the Fanconi anemia pathway
        is the
- 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) support for FANCA membership in the FA nuclear complex,
      consistent with the IBA/IDA/NAS evidence.
    action: ACCEPT
    reason: Correct and central cellular-component annotation; FANCA is a defining subunit
      of the FA core complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10627486
  qualifier: enables
  review:
    summary: Yeast two-hybrid interaction between FANCA and FANCG. FANCA-FANCG is one
      of the strongest and most direct interactions within the FA core complex, but
      the GO term captured (protein binding) is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction is real and biologically meaningful (FANCA-FANCG),
      but GO:0005515 protein binding is an uninformative molecular-function term. FANCA's
      scaffold/adaptor role is captured in core_functions.
    supported_by:
    - reference_id: PMID:10627486
      supporting_text: 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 evidence for a strong, direct FANCA-FANCG interaction.
      Real interaction but uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 protein binding is uninformative. The FANCA-FANCG interaction
      is captured in the description/core_functions as part of the core-complex scaffold.
    supported_by:
    - reference_id: PMID:10652215
      supporting_text: indicating strong, direct interaction between these proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11063725
  qualifier: enables
  review:
    summary: FANCA co-complexes with FANCC, FANCF and FANCG in the nucleus. Real complex
      membership but annotated only as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative MF term; the FANCA-FANCF/FANCG/FANCC associations are core-complex
      relationships better captured by the FA nuclear complex CC annotation and core_functions.
    supported_by:
    - reference_id: PMID:11063725
      supporting_text: where it complexes with FANCA, FANCC and
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12649160
  qualifier: enables
  review:
    summary: Yeast two/three-hybrid mapping showing FANCG interacts with the amino-terminus
      of FANCA and that FANCG bridges FANCA-FANCF. Real interactions, uninformative MF
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 protein binding is uninformative; the mapped FANCA-FANCG/FANCF
      contacts define core-complex architecture and are captured elsewhere.
    supported_by:
    - reference_id: PMID:12649160
      supporting_text: FANCG was shown to interact with both
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Large-scale (proteome-scale) human protein-protein interaction mapping;
      the recorded FANCA partner is FANCG. High-throughput evidence for generic protein
      binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome data annotated as generic protein binding is
      uninformative for molecular function. The FANCA-FANCG interaction itself is already
      well established.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17289582
  qualifier: enables
  review:
    summary: Study identifying FAAP24 as an FA core-complex protein that (via FANCM)
      links the complex to damaged DNA; the recorded FANCA interactant here is FANCG.
      Annotated as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction is genuine core-complex biology, but GO:0005515 is uninformative.
      Captured in core_functions/CC annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17396147
  qualifier: enables
  review:
    summary: FAAP100 (and FANCG) interactions; FAAP100 is essential for activation of
      the FA DNA-damage-response pathway and is an integral core-complex protein. Annotated
      as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Real core-complex interaction but uninformative MF term. FANCA's role as
      an interaction hub is captured in core_functions.
    supported_by:
    - reference_id: PMID:17396147
      supporting_text: FAAP100 is essential for activation of the Fanconi anemia-associated
        DNA damage
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17474147
  qualifier: enables
  review:
    summary: SH3-domain peptide-array screen recording a FANCA-GRB2 interaction. This
      is a systematic domain-ligand screen, peripheral to FANCA's core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput peptide-array interaction annotated as generic protein binding;
      uninformative and peripheral (GRB2 is not part of the FA core complex).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22266823
  qualifier: enables
  review:
    summary: FAAP20 (Q6NZ36) binds directly to the FANCA subunit and is required for
      stability of the core complex and FANCD2 monoubiquitination. Direct and functionally
      important, but annotated as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: The FANCA-FAAP20 interaction is direct and biologically central, but GO:0005515
      is uninformative. FANCA's role as the FAAP20 docking subunit is captured in core_functions.
    supported_by:
    - reference_id: PMID:22266823
      supporting_text: multisubunit Fanconi anemia core complex. FAAP20 binds to FANCA
        subunit and is
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Architecture-of-the-human-interactome study; recorded FANCA partner is FANCG.
      High-throughput protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome evidence annotated as generic protein binding
      is uninformative for molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Interactome-mapping study (neurodegenerative-disease network); recorded
      FANCA partner is FANCG. High-throughput protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome data annotated as generic protein binding; uninformative
      MF term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Dual proteome-scale interaction network (BioPlex); recorded FANCA partner
      is FANCG. High-throughput protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome evidence annotated as generic protein binding;
      uninformative MF term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: OpenCell endogenous-tagging cartography; recorded FANCA partner is FAAP100.
      High-throughput protein binding consistent with core-complex membership.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput proteomics annotated as generic protein binding; uninformative
      MF term although the FAAP100 association is consistent with the known complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37398436
  qualifier: enables
  review:
    summary: AI-guided PPI drug-discovery pipeline recording a FANCA-FANCG interaction.
      High-throughput/computational-plus-experimental protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding term; uninformative for molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interactome study; recorded FANCA partner is FANCG.
      High-throughput protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome data annotated as generic protein binding; uninformative
      MF term.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (Human Protein Atlas) localizes FANCA to the nucleoplasm,
      consistent with the nuclear site of action of the FA core complex.
    action: ACCEPT
    reason: Direct immunofluorescence evidence for nucleoplasmic localization; consistent
      with the functional nuclear compartment of FANCA.
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:22343915
  qualifier: located_in
  review:
    summary: FANCA undergoes DNA-damage-induced chromatin loading (dependent on the FAAP20
      UBZ domain), placing it at chromatin where crosslink repair is initiated.
    action: ACCEPT
    reason: Direct evidence that FANCA is loaded onto chromatin after DNA damage; a functionally
      relevant location for the FA core complex.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: but is required for DNA-damage-induced chromatin loading of FANCA
        and the
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: NAS
  original_reference_id: PMID:19965384
  qualifier: involved_in
  review:
    summary: The FA pathway (of which FANCA is a core-complex subunit) promotes replication-dependent
      repair of DNA interstrand crosslinks via monoubiquitination of FANCI-FANCD2. Core
      biological process.
    action: ACCEPT
    reason: Well-supported core process for FANCA. Consistent with the IEA ICL-repair
      annotation and the broader DNA-repair role.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: hypersensitivity to chemicals that generate DNA interstrand cross-links
        (ICLs)
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: NAS
  original_reference_id: PMID:22343915
  qualifier: part_of
  review:
    summary: FAAP20 study confirming FANCA as an integral component of the FA nuclear
      core complex, with a defined FANCA region binding FAAP20.
    action: ACCEPT
    reason: Directly supports FANCA membership in the FA nuclear complex; core CC annotation.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: that FAAP20 is an integral component of the FA nuclear core complex.
        We identify
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835411
  qualifier: located_in
  review:
    summary: Reactome places FANCA (in a core-complex:HSP70 assembly binding PKR) in
      the cytosol. This reflects a cytoplasmic/pre-assembly pool rather than the functional
      nuclear site.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization is consistent with the known minor cytoplasmic pool
      of FANCA, but the core DNA-repair function occurs in the nucleus; keep as non-core.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785126
  qualifier: located_in
  review:
    summary: Reactome (FA core complex assembles at ICLs) localizes FANCA to the nucleoplasm,
      the functional compartment of the FA pathway.
    action: ACCEPT
    reason: Consistent with the nucleoplasmic site of FA core-complex action; supported
      by IDA localization evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785342
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm annotation for FANCA within the FA/ICL-repair reaction
      set.
    action: ACCEPT
    reason: Correct functional location; consistent with other nucleoplasm evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785361
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm annotation for FANCA within the FANCD2:FANCI monoubiquitination
      reaction context.
    action: ACCEPT
    reason: Correct functional location; consistent with other nucleoplasm evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm annotation for FANCA in the ICL-repair reaction set.
    action: ACCEPT
    reason: Correct functional location; consistent with other nucleoplasm evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm annotation for FANCA in the ICL-unhooking reaction
      set.
    action: ACCEPT
    reason: Correct functional location; consistent with other nucleoplasm evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786155
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm annotation for FANCA in the ICL-repair reaction set.
    action: ACCEPT
    reason: Correct functional location; consistent with other nucleoplasm evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786166
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm annotation for FANCA in the translesion-synthesis reaction
      context.
    action: ACCEPT
    reason: Correct functional location; consistent with other nucleoplasm evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786171
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm annotation for FANCA in the FANCD2-deubiquitination
      reaction context.
    action: ACCEPT
    reason: Correct functional location; consistent with other nucleoplasm evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788385
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm annotation for FANCA in the ATR/ATRIP recruitment reaction
      context.
    action: ACCEPT
    reason: Correct functional location; consistent with other nucleoplasm evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788392
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm annotation for FANCA in the ATR-phosphorylation reaction
      context.
    action: ACCEPT
    reason: Correct functional location; consistent with other nucleoplasm evidence.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22343915
  qualifier: enables
  review:
    summary: Direct interaction between FANCA and FAAP20/C1orf86; FANCA regulates FAAP20
      stability. Direct and functionally important, annotated as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: The FANCA-FAAP20 interaction is direct and central to core-complex integrity,
      but GO:0005515 is uninformative. Captured in core_functions.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: a region on FANCA that physically interacts with FAAP20, and show
        that FANCA
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22705371
  qualifier: enables
  review:
    summary: FAAP20 (a component of the FA core complex, bound by FANCA) links RNF8-mediated
      ubiquitination to the FA network. Annotated as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Real, functionally important core-complex interaction, but GO:0005515 is
      uninformative for molecular function.
    supported_by:
    - reference_id: PMID:22705371
      supporting_text: by RNF8 and its partner, UBC13, and mediated by FAAP20, a component
        of the FA
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:22266823
  qualifier: part_of
  review:
    summary: Direct identification of FANCA within the multisubunit FA core complex (Rev1-regulation
      study identifying FAAP20 as an integral subunit binding FANCA).
    action: ACCEPT
    reason: Direct experimental evidence for FANCA membership in the FA core complex;
      core CC annotation.
    supported_by:
    - reference_id: PMID:22266823
      supporting_text: multisubunit Fanconi anemia core complex. FAAP20 binds to FANCA
        subunit and is
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:22343915
  qualifier: part_of
  review:
    summary: Direct evidence that FANCA is an integral component of the FA nuclear core
      complex (FAAP20 study).
    action: ACCEPT
    reason: Direct experimental support for the core CC annotation.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: that FAAP20 is an integral component of the FA nuclear core complex.
        We identify
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:22705371
  qualifier: part_of
  review:
    summary: FANCA identified as part of the FA core complex whose recruitment to ICLs
      is regulated by the RNF8-FAAP20 ubiquitin cascade.
    action: ACCEPT
    reason: Direct experimental support for FANCA membership in the FA nuclear 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 histone-fold complex study in which FANCA is identified as part
      of the FA core complex.
    action: ACCEPT
    reason: Direct experimental support for the core CC annotation; consistent with all
      other complex-membership evidence.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11726552
  qualifier: enables
  review:
    summary: FANCA associates with BRG1/SMARCA4 (a subunit of the SWI/SNF chromatin-remodeling
      complex) and co-localizes with it in the nucleus. Real interaction, uninformative
      MF term; a proposed link to chromatin remodeling/transcription.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 protein binding is uninformative. The FANCA-BRG1/SWI-SNF interaction
      is a plausible but secondary/peripheral activity relative to the core FA-complex
      DNA-repair function.
    supported_by:
    - reference_id: PMID:11726552
      supporting_text: FANCA was demonstrated to associate with the endogenous SWI/SNF
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11726552
  qualifier: located_in
  review:
    summary: Direct evidence of nuclear localization of FANCA (co-localization with BRG1
      in the nucleus).
    action: ACCEPT
    reason: Direct experimental support for the functional nuclear localization of FANCA.
    supported_by:
    - reference_id: PMID:11726552
      supporting_text: between transfected FANCA and BRG1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12571280
  qualifier: enables
  review:
    summary: FANCA co-immunoprecipitates with nonerythroid alphaII-spectrin and ERCC4/XPF
      and is recruited to ICL-induced nuclear foci. Real interaction relevant to ICL
      repair, but annotated as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: The FANCA-spectrin-XPF interactions are functionally relevant to recruitment
      at crosslink damage, but GO:0005515 is uninformative for molecular function.
    supported_by:
    - reference_id: PMID:12571280
      supporting_text: alphaSpIISigma*, FANCA and XPF co-immunoprecipitate with each
        other from normal
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:9398857
  qualifier: located_in
  review:
    summary: The FAA-FAC (FANCA-FANCC) complex is found in the nucleus (as well as cytoplasm);
      nuclear localization is essential for FA-pathway function.
    action: ACCEPT
    reason: Supports the functional nuclear localization of FANCA; consistent with IEA/IDA
      nucleus evidence.
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: is found in similar abundance in both cytoplasm and nucleus
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:9398857
  qualifier: located_in
  review:
    summary: Unbound FANCA/FANCC localize predominantly to the cytoplasm; a minor cytoplasmic
      pool exists. Non-core (pre-assembly/inactive) location.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization is documented but does not represent the functional
      nuclear site of FANCA action; keep as non-core, consistent with the IEA cytoplasm
      annotation.
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: unbound FAA and FAC localize predominantly to the cytoplasm, the
        FAA-FAC complex
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: TAS
  original_reference_id: PMID:8896564
  qualifier: involved_in
  review:
    summary: FANCA was cloned as an FA group A gene and proposed to belong to a class
      of genes associated with prevention/repair of DNA damage. Correct, broader parent
      of the more specific interstrand cross-link repair.
    action: ACCEPT
    reason: DNA repair is an accurate (if general) biological-process annotation for FANCA;
      it is broader than but consistent with the ICL-repair annotation, and it is acceptable
      to retain the parent term.
    supported_by:
    - reference_id: PMID:8896564
      supporting_text: new class of genes associated with the prevention or repair of
        DNA damage
- term:
    id: GO:0065003
    label: protein-containing complex assembly
  evidence_type: TAS
  original_reference_id: PMID:9398857
  qualifier: involved_in
  review:
    summary: FANCA is required for formation and stability of the FA core complex (it
      binds FANCG/FANCF, anchors and stabilizes FAAP20, and the FAA-FAC complex forms
      only in functional cells). Assembly of the multiprotein complex is a genuine role.
    action: ACCEPT
    reason: FANCA participates directly in assembly of the FA core complex; supported
      by demonstration that FANCA and FANCC bind each other and form a complex, and by
      FANCA-dependent stability of core-complex partners.
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: the FAA and FAC bind each other and form a complex
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IPI
  original_reference_id: PMID:22266823
  qualifier: enables
  review:
    summary: Proposed informative molecular-function annotation replacing the uninformative
      protein binding calls. FANCA acts as a scaffold/adaptor that brings together core-complex
      subunits (binds FANCG/FANCF and directly anchors FAAP20), coordinating assembly
      and function of the FA core complex.
    action: NEW
    reason: FANCA is a non-catalytic scaffolding subunit whose defining biochemical activity
      is bridging protein partners within the FA core complex; the many FANCA IPI annotations
      to generic protein binding (e.g. FANCG, FANCF, FAAP20) are better represented by
      an adaptor activity. FAAP20 binds directly to the FANCA subunit and FANCA is required
      for complex stability.
    supported_by:
    - reference_id: PMID:22266823
      supporting_text: multisubunit Fanconi anemia core complex. FAAP20 binds to FANCA
        subunit and is
    - reference_id: PMID:22343915
      supporting_text: a region on FANCA that physically interacts with FAAP20, and show
        that FANCA
- term:
    id: GO:0003697
    label: single-stranded DNA binding
  evidence_type: IDA
  original_reference_id: PMID:22194614
  qualifier: enables
  review:
    summary: Purified FANCA has an intrinsic nucleic-acid-binding activity with preference
      for single-stranded over double-stranded DNA (and RNA > ssDNA > dsDNA), mapped
      to its C-terminal domain where most disease mutations cluster. This activity is
      absent from the curated GOA set; it is added here as a well-documented but single-lab
      intrinsic activity surfaced by the Affinage record.
    action: NEW
    reason: Two primary papers from one group (Zhang lab) show purified FANCA directly
      binds ssDNA by EMSA, with a patient-derived truncation (Q772X) deficient and the
      C-terminal fragment C772-1455 retaining binding. This intrinsic ssDNA-binding
      activity is proposed to help recruit and assemble the FA core complex at stalled
      replication forks. It is a real biochemical activity but has not been independently
      replicated or adopted by GO curators, so it is treated as a non-core molecular function.
    supported_by:
    - reference_id: PMID:22194614
      supporting_text: Using purified protein, we report that human FANCA has intrinsic
        affinity for nucleic acids.
    - reference_id: PMID:22194614
      supporting_text: its affinity for ssDNA is significantly higher than for dsDNA
        in an electrophoretic mobility shift assay
- term:
    id: GO:0045002
    label: double-strand break repair via single-strand annealing
  evidence_type: IMP
  original_reference_id: PMID:30057198
  qualifier: involved_in
  review:
    summary: Beyond its canonical core-complex scaffold role, purified FANCA catalyzes
      single-strand annealing and strand exchange comparable to RAD52, and cell-based
      DSB-repair assays (siRNA knockdown, CRISPR knockout, mutant complementation) show
      FANCA is specifically required for the single-strand-annealing sub-pathway of DSB
      repair, independently of the canonical FA pathway and RAD52. Not present in the
      curated GOA set.
    action: NEW
    reason: PMID:30057198 (Mol Cell) demonstrates FANCA SA/SE activity in vitro (with
      a homodimerization requirement, and six patient-derived mutants deficient) and a
      direct cellular role in the SSA sub-pathway of DSB repair that is distinct from
      FANCD2 monoubiquitination. GO:0045002 is a real, correctly-branched biological-process
      term. This is a well-documented but single-lab, non-canonical activity absent from
      the curated annotations; added as non-core.
    supported_by:
    - reference_id: PMID:30057198
      supporting_text: The SA and SE activities of FANCA directly explain its role in
        homology-directed DSB repair.
    - reference_id: PMID:30057198
      supporting_text: Our cell-based DSB repair assay further demonstrates that FANCA
        contributes to the repair of DNA double strand breaks independently of the FA
        pathway and RAD52 in human cells.
core_functions:
- description: As an essential, non-catalytic structural subunit and protein-interaction
    hub of the multiprotein Fanconi anemia (FA) core complex, FANCA acts as a scaffold/adaptor
    that binds FANCG and FANCF and directly anchors FAAP20, promoting assembly, stability,
    nuclear accumulation and chromatin loading of the core complex so that it can monoubiquitinate
    the FANCD2-FANCI complex during replication-coupled repair of DNA interstrand crosslinks.
  supported_by:
  - reference_id: PMID:22266823
    supporting_text: multisubunit Fanconi anemia core complex. FAAP20 binds to FANCA
      subunit and is
  - reference_id: PMID:22343915
    supporting_text: a region on FANCA that physically interacts with FAAP20, and show
      that FANCA
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  directly_involved_in:
  - id: GO:0036297
    label: interstrand cross-link repair
  - id: GO:0065003
    label: protein-containing complex assembly
  in_complex:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  locations:
  - id: GO:0005654
    label: nucleoplasm
  - id: GO:0000785
    label: chromatin
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: PMID:10627486
  title: Strong FANCA/FANCG but weak FANCA/FANCC interaction in the yeast 2-hybrid
    system.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract verified; documents a strong direct FANCA-FANCG interaction,
      a core intra-complex contact. Supports interaction but only generic protein-binding
      GO term.
- id: PMID:10652215
  title: Investigation of Fanconi anemia protein interactions by yeast two-hybrid
    analysis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract verified; strong direct FANCA-FANCG interaction (no direct
      FANCA-FANCC interaction detected by Y2H). Consistent with core-complex architecture.
- 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: Abstract verified; establishes the nuclear FANCA/FANCC/FANCF/FANCG
      complex, a foundational description of the FA core complex.
- id: PMID:11726552
  title: Fanconi anemia protein, FANCA, associates with BRG1, a component of the human
    SWI/SNF complex.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract verified; documents FANCA-BRG1/SWI-SNF association and nuclear
      co-localization. Supports nuclear localization (IDA) and a peripheral chromatin-remodeling
      link.
- id: PMID:12571280
  title: Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF
    to nuclear foci induced by DNA interstrand cross-links.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract verified; FANCA co-IPs with alphaII-spectrin and XPF and
      is recruited to ICL-induced nuclear foci. Relevant to recruitment at crosslink
      damage.
- id: PMID:12649160
  title: 'Fanconi anemia protein complex: mapping protein interactions in the yeast
    2- and 3-hybrid systems.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract verified; maps FANCA-FANCG contacts and FANCG bridging of
      FANCA-FANCF, and notes the FANCA/C/E/F/G complex is required for FANCD2 monoubiquitination.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome map; FANCA-FANCG edge. Supports only
      generic protein binding.
- id: PMID:17289582
  title: Identification of FAAP24, a Fanconi anemia core complex protein that interacts
    with FANCM.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract verified; identifies FAAP24 as a core-complex protein linking
      FANCM to damaged DNA. FANCA is a co-recorded interactant; supports core-complex
      biology.
- id: PMID:17396147
  title: FAAP100 is essential for activation of the Fanconi anemia-associated DNA
    damage response pathway.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract verified; FAAP100 is an integral core-complex protein essential
      for FA-pathway activation. Relevant to core-complex composition.
- id: PMID:17474147
  title: Systematic identification of SH3 domain-mediated human protein-protein interactions
    by peptide array target screening.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput SH3-domain peptide-array screen (FANCA-GRB2). Peripheral;
      supports only generic protein binding.
- 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: Abstract verified; establishes that the FA pathway (monoubiquitinated
      FANCI-FANCD2) drives replication-coupled ICL repair. Core biological-process context
      for FANCA.
- id: PMID:20347428
  title: A histone-fold complex and FANCM form a conserved DNA-remodeling complex
    to maintain genome stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract verified; FANCM-MHF DNA-remodeling complex within the FA
      core complex. Supports FANCA complex-membership context.
- 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; identifies FAAP20 as an integral core-complex
      subunit binding FANCA, required for complex stability and FANCD2 monoubiquitination,
      and links the FA core to TLS. Strong support for FANCA scaffold/adaptor role.
- 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: Abstract verified; FAAP20 is an integral FA nuclear core-complex protein;
      a region of FANCA binds FAAP20 and FANCA regulates its stability; FAAP20 UBZ required
      for DNA-damage-induced chromatin loading of FANCA.
- id: PMID:22705371
  title: A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to
    the Fanconi anemia DNA repair network.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract verified; FAAP20 (bound by FANCA) links RNF8-UBC13 ubiquitin
      signaling to recruitment of the FA core complex and FANCD2 to ICLs.
- id: PMID:22194614
  title: Fanconi anemia complementation group A (FANCA) protein has intrinsic affinity
    for nucleic acids with preference for single-stranded forms.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text (PMC) verified; purified FANCA binds nucleic acids with
      preference ssDNA over dsDNA and RNA over DNA, C-terminal binding domain, patient
      truncation Q772X deficient. A single-lab intrinsic activity not in the curated
      GOA; supports a NEW single-stranded DNA binding annotation as a non-core activity.
- id: PMID:30057198
  title: FANCA Promotes DNA Double-Strand Break Repair by Catalyzing Single-Strand
    Annealing and Strand Exchange.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text (PMC) verified; purified FANCA catalyzes single-strand
      annealing and strand exchange comparable to RAD52 (homodimer-dependent), six
      patient mutants deficient, and cell-based assays show a direct SSA-sub-pathway
      DSB-repair role independent of the canonical FA pathway and RAD52. Single-lab
      but well-controlled; supports a NEW GO:0045002 annotation as a non-core activity.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome (BioPlex); FANCA-FANCG edge. Supports
      only generic protein binding.
- 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: High-throughput interactome study; FANCA-FANCG edge. Peripheral;
      supports only generic protein binding.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome (BioPlex 3.0); FANCA-FANCG edge. Supports
      only generic protein binding.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput endogenous-tagging proteomics; FANCA-FAAP100 association
      consistent with core complex. Supports only generic protein binding.
- id: PMID:37398436
  title: AI-guided pipeline for protein-protein interaction drug discovery identifies
    a SARS-CoV-2 inhibitor.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput/AI-guided PPI pipeline; FANCA-FANCG edge. Supports
      only generic protein binding.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput multimodal cell-map interactome; FANCA-FANCG edge.
      Supports only generic protein binding.
- id: PMID:8896564
  title: Positional cloning of the Fanconi anaemia group A gene.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract verified; original positional cloning of FANCA (1,455 aa)
      as an FA group A gene linked to prevention/repair of DNA damage.
- id: PMID:9398857
  title: The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract verified; foundational demonstration that FANCA (FAA) and
      FANCC (FAC) bind and form a complex present in both cytoplasm and nucleus; unbound
      forms are predominantly cytoplasmic.
- 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: []

FANCA

Gene Description