FANCC

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0034599 cellular response to oxidative stress	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically inferred oxidative-stress response, driven largely by mouse Fancc knockout data. FANCC/FA-deficient cells show hypersensitivity to oxidative stress and FANCC has proposed redox-regulatory/detoxification roles, but this is peripheral to and separable from its core ICL-repair function. Reason: A genuine but context-specific/secondary role. FANCC's core molecular role is as a structural subunit of the FA core E3 ligase; oxidative-stress protection is a downstream/indirect consequence and is structurally separable from the cross-linker-resistance function (mutations that disrupt cytokine/stress signaling still complement MMC sensitivity and FANCD2 activation). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000423656 · FANCC family node SUPPORTS TRANSFER Redox/oxidative-stress phenotype supported mainly by mouse Fancc (MGI:95480) knockouts; a real but non-core, downstream role. Supporting Evidence: PMID:11520787 All mutants complemented mitomycin C (MMC) hypersensitive phenotype of FA-C cells and corrected aberrant posttranslational activation of FANCD2 in FA-C mutant cells. However, 2 of the mutants, S249A and E251A, failed to correct defective STAT1 activation. PMID:9787138 We propose that FAC plays a fundamental role in vivo by attenuating the activity of RED, thereby regulating a major detoxification pathway in mammalian cells.
GO:0006289 nucleotide-excision repair	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: FANCC is not a canonical nucleotide-excision repair (NER) factor. The FA pathway coordinates incision, homologous recombination and translesion synthesis during interstrand cross-link repair, and can intersect with NER machinery, but FANCC itself has no NER enzymatic role. Reason: Likely an over-propagated phylogenetic inference. The correct, well-supported process for FANCC is interstrand cross-link repair (GO:0036297), which is separately annotated; annotating classical NER over-states FANCC's role. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION GRANULARITY MISMATCH Sources checked: PANTHER:PTN000423656 · FANCC family node SUPPORTS SOURCE BUT NOT TARGET The FA pathway can intersect NER machinery during ICL processing, but FANCC is not a nucleotide-excision-repair factor; ICL repair (GO:0036297) is the correct process. Supporting Evidence: PMID:19965384 FANCI-FANCD2 is required for replication-coupled ICL repair in S phase.
GO:0043240 Fanconi anaemia nuclear complex	IBA GO_REF:0000033	ACCEPT	Summary: FANCC is a core subunit of the Fanconi anemia nuclear (core) complex, together with FANCA, FANCB, FANCE, FANCF, FANCG, FANCL and FANCM. This is a core, well-established annotation. Reason: Strongly supported by phylogenetic inference and by direct experimental co-purification of FANCC with other FA core subunits; FANCC-FANCE-FANCF form the substrate-recognition module of the complex. Supporting Evidence: PMID:12649160 The FANCA, FANCC, FANCE, FANCF, and FANCG proteins form a nuclear complex required for the monoubiquination of the FANCD2 protein. PMID:22266823 Flag-tagged FAAP20 co-immunoprecipitated with FANCA, FANCE, and FANCC, indicating that FAAP20 associates with the FA core complex
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: FANCC localizes to the nucleus; the assembled FA core complex acts in the nucleoplasm and on chromatin. UniProt records the major form as nuclear. Reason: Consistent with subcellular-location mapping and with experimental data showing the assembled FAA-FAC complex is abundant in the nucleus. Supporting Evidence: PMID:9398857 the FAA-FAC complex is found in similar abundance in both cytoplasm and nucleus.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: FANCC has a well-documented minor cytoplasmic form; unbound FANCC/FANCA are largely cytoplasmic and the cytosolic pool associates with chaperones (GRP94) and a PKR/HSP70 complex. Reason: Supported by multiple localization studies; UniProt lists Cytoplasm as a location (the minor form is cytoplasmic). Supporting Evidence: PMID:9398857 Although unbound FAA and FAC localize predominantly to the cytoplasm, the FAA-FAC complex is found in similar abundance in both cytoplasm and nucleus.
GO:0036297 interstrand cross-link repair	IEA GO_REF:0000002	ACCEPT	Summary: FANCC, as part of the FA core complex, is required for the FANCD2-FANCI monoubiquitination that drives replication-coupled DNA interstrand cross-link repair. This is a core function. Reason: Well supported; ICL repair is the defining process of the FA pathway and FANCC deficiency causes cross-linker hypersensitivity. Supporting Evidence: PMID:19965384 A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex PMID:22266823 the FA proteins cooperate in a DNA damage response (DDR) pathway required for DNA interstrand crosslink repair
GO:0043240 Fanconi anaemia nuclear complex	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based inference that FANCC is part of the FA nuclear complex; consistent with the FANCC domain signature and with experimental data. Reason: Correct and core; redundant with the experimental part_of annotations but appropriately captures complex membership. Supporting Evidence: PMID:12649160 The FANCA, FANCC, FANCE, FANCF, and FANCG proteins form a nuclear complex required for the monoubiquination of the FANCD2 protein.
GO:0005515 protein binding	IPI PMID:12649160 Fanconi anemia protein complex: mapping protein interactions...	MARK AS OVER ANNOTATED	Summary: IPI capturing the direct FANCC-FANCE interaction (WITH UniProtKB:Q9HB96 = FANCE) mapped by yeast two-hybrid. This is a functionally meaningful, core-complex interaction (a central region of FANCE binds FANCC; L554P abolishes it), but the GO term protein binding itself is uninformative. Reason: GO:0005515 conveys no specific molecular function. The biologically meaningful content (FANCC-FANCE module of the FA core complex) is captured by the Fanconi anaemia nuclear complex annotations and by the molecular adaptor / ubiquitin-ligase core function. Supporting Evidence: PMID:12649160 A central region of FANCE was sufficient for FANCC binding. A Leu554Pro mutant of FANCC failed to interact with FANCE.
GO:0005515 protein binding	IPI PMID:24412244 Charting the molecular links between driver and susceptibili...	MARK AS OVER ANNOTATED	Summary: High-throughput/network interactions (WITH SMAD4 Q13485 and FBXW7 Q969H0) from a colorectal-cancer driver/susceptibility interactome. Uninformative and not established as functionally relevant to FANCC's DNA-repair role. Reason: The term protein binding is uninformative; these are large-scale network interactions of low specificity for FANCC function.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	MARK AS OVER ANNOTATED	Summary: High-throughput two-hybrid interaction (WITH MEOX2 Q6FHY5) from an alternative-splicing interactome map. Uninformative for FANCC's core function. Reason: Uninformative GO term captured by a large-scale interactome screen; no evidence this interaction is relevant to FANCC's ICL-repair role.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Affinity-purification (BioPlex) interaction (WITH FANCE Q9HB96). Recovers the genuine FANCC-FANCE core-complex partnership but via an uninformative GO term. Reason: The FANCE partnership is real and core, but is better represented by the FA nuclear complex annotations; GO:0005515 itself adds no functional information.
GO:0005515 protein binding	IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei...	MARK AS OVER ANNOTATED	Summary: Interactions (WITH AKT1 P31749, SMAD4 Q13485, FBXW7 Q969H0) from a systematic mutation-directed neo-PPI screen in cancer. Uninformative and not tied to FANCC's canonical function. Reason: Large-scale screen interactions with an uninformative GO term; low specificity for FANCC biology.
GO:0005515 protein binding	IPI PMID:9596688 Molecular chaperone GRP94 binds to the Fanconi anemia group ...	MARK AS OVER ANNOTATED	Summary: IPI capturing the FANCC-GRP94/HSP90B1 (P14625) interaction. GRP94 is a cytosolic chaperone that binds FANCC and regulates its steady-state level; this is a stability/localization interaction rather than a distinct catalytic function. Reason: The term protein binding is uninformative. The functional content (chaperone-mediated regulation of FANCC abundance in the cytosol) is peripheral to the core FA-pathway function. Supporting Evidence: PMID:9596688 Binding was confirmed by coimmunoprecipitation of FAC and GRP94 from cytosolic, but not nuclear, lysates
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence (HPA) localizes FANCC to the nucleoplasm, consistent with the nuclear site of FA core complex action. Reason: Direct experimental localization; consistent with the nuclear FA-pathway function.
GO:0000785 chromatin	IDA PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr...	ACCEPT	Summary: The FA core complex undergoes DNA-damage-induced chromatin loading; FANCC is annotated to chromatin as a complex member (ComplexPortal IDA). Reason: Supported by evidence that core-complex chromatin loading is required for FA-pathway function; FANCC acts on chromatin as part of the complex. Supporting Evidence: PMID:22343915 is required for DNA-damage-induced chromatin loading of FANCA and the functional integrity of the FA pathway.
GO:0036297 interstrand cross-link repair	NAS PMID:19965384 The Fanconi anemia pathway promotes replication-dependent DN...	ACCEPT	Summary: Author statement (ComplexPortal NAS) that the FA pathway, including FANCC, promotes replication-dependent ICL repair. Core function, consistent with the IEA annotation of the same term. Reason: Core process for FANCC; the FA pathway is required for replication-coupled ICL repair. Supporting Evidence: PMID:19965384 multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.
GO:0043240 Fanconi anaemia nuclear complex	NAS PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr...	ACCEPT	Summary: Author statement that FANCC is part of the FA nuclear core complex, whose integrity is required for the FA-BRCA DNA repair pathway. Reason: Core complex membership, consistent with experimental co-purification. Supporting Evidence: PMID:22343915 We show that FAAP20 is an integral component of the FA nuclear core complex.
GO:0005829 cytosol	TAS Reactome:R-HSA-9835411	ACCEPT	Summary: Reactome localizes a cytosolic FA core complex:HSP70:PKR assembly. Consistent with the documented minor cytoplasmic form of FANCC and its cytosolic PKR/HSP70 interactions. Reason: Supported by the well-established cytoplasmic pool of FANCC; a valid, non-core location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785126	ACCEPT	Summary: Reactome nucleoplasm location for FANCC as the FA core complex assembles at ICLs. Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785342	ACCEPT	Summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series. Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785361	ACCEPT	Summary: Reactome nucleoplasm location for FANCC (monoubiquitination of FANCD2-FANCI step). Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785732	ACCEPT	Summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series. Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785986	ACCEPT	Summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series. Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6786155	ACCEPT	Summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series. Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6786166	ACCEPT	Summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series. Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6786171	ACCEPT	Summary: Reactome nucleoplasm location for FANCC (FANCD2 deubiquitination step context). Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6788385	ACCEPT	Summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series. Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6788392	ACCEPT	Summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series. Reason: Consistent with nuclear action of the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6806425	ACCEPT	Summary: Reactome nucleoplasm location for FANCC (TP53 stimulates FANCC expression context). Reason: Consistent with nuclear action of the FA core complex.
GO:0043240 Fanconi anaemia nuclear complex	IDA PMID:22266823 Regulation of Rev1 by the Fanconi anemia core complex.	ACCEPT	Summary: Direct experimental identification of FANCC in the FA core complex (co-immunoprecipitation with FANCA and FANCE). Core complex membership. Reason: Direct experimental evidence for FANCC as an integral FA core complex subunit. Supporting Evidence: PMID:22266823 Flag-tagged FAAP20 co-immunoprecipitated with FANCA, FANCE, and FANCC, indicating that FAAP20 associates with the FA core complex
GO:0043240 Fanconi anaemia nuclear complex	IDA PMID:20347428 A histone-fold complex and FANCM form a conserved DNA-remode...	ACCEPT	Summary: Direct experimental identification of FANCC as part of the FA nuclear complex in the context of the MHF (histone-fold)-FANCM DNA-remodeling module study. Reason: Direct evidence supporting FANCC as a core complex subunit; do not overrule the experimental curation.
GO:0005829 cytosol	IDA PMID:9596688 Molecular chaperone GRP94 binds to the Fanconi anemia group ...	ACCEPT	Summary: FANCC (FAC) was directly detected in cytosolic lysates by co-immunoprecipitation with the chaperone GRP94, consistent with a cytoplasmic pool of FANCC. Reason: Direct experimental localization to the cytosol; supports the documented minor cytoplasmic form. Supporting Evidence: PMID:9596688 Binding was confirmed by coimmunoprecipitation of FAC and GRP94 from cytosolic, but not nuclear, lysates
GO:0005634 nucleus	TAS PMID:9398857 The Fanconi anaemia proteins, FAA and FAC, interact to form ...	ACCEPT	Summary: The assembled FAA-FAC (FANCA-FANCC) complex is found abundantly in the nucleus, supporting nuclear localization. Reason: Supported by direct study of the FAA-FAC nuclear complex. Supporting Evidence: PMID:9398857 the FAA-FAC complex 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 ...	ACCEPT	Summary: Unbound FANCC (and FANCA) localize predominantly to the cytoplasm; the cytoplasmic form is well documented. Reason: Supported by direct localization data on the FAA/FAC proteins. Supporting Evidence: PMID:9398857 Although unbound FAA and FAC localize predominantly to the cytoplasm
GO:0006281 DNA repair	TAS PMID:1574115 Cloning of cDNAs for Fanconi's anaemia by functional complem...	ACCEPT	Summary: FANCC was cloned by functional complementation of the FA cross-linker-hypersensitivity phenotype, establishing its role in DNA repair. This general term is correct though less specific than interstrand cross-link repair. Reason: Correct high-level process; retained as a valid general parent alongside the more specific ICL-repair annotation. Supporting Evidence: PMID:1574115 Cloning of cDNAs for Fanconi's anaemia by functional complementation.
GO:0065003 protein-containing complex assembly	TAS PMID:9398857 The Fanconi anaemia proteins, FAA and FAC, interact to form ...	ACCEPT	Summary: FANCC-FANCA binding nucleates the nuclear FA complex; FANCC is required for assembly and integrity of the FA core complex, and the L554P mutant fails to bind FANCA and cannot form the functional complex. Reason: Supported by direct demonstration that FANCC binding to FANCA is required to form the functional nuclear complex, i.e. FANCC participates in complex assembly. Supporting Evidence: PMID:9398857 we demonstrate the FAA and FAC bind each other and form a complex. Protein binding correlates with the functional activity of FAA and FAC, as patient-derived mutant FAC (L554P) fails to bind FAA. PMID:11063725 This implies that each of the FA proteins, except FANCD, is required for these complexes to form.
GO:0030674 protein-macromolecule adaptor activity	IPI PMID:12649160 Fanconi anemia protein complex: mapping protein interactions...	NEW	Summary: Proposed informative molecular function replacing the uninformative 'protein binding' IPI annotations. FANCC acts as a non-catalytic molecular adaptor within the FA core complex substrate-recognition module: it binds FANCE directly and, with FANCF, bridges the catalytic FANCL/UBE2T module to the FANCD2-FANCI substrate. Cryo-EM shows FANCC-FANCE-FANCF constitute the single-copy substrate-recognition module of the complex. Reason: FANCC has no catalytic activity; its function is to bind and bridge partners (FANCE, and via assembly FANCA) so the complex can recognize and monoubiquitinate FANCD2-FANCI. Molecular adaptor activity is a more informative MF than 'protein binding' and underpins the ubiquitin-ligase core function. Supporting Evidence: PMID:12649160 A central region of FANCE was sufficient for FANCC binding. A Leu554Pro mutant of FANCC failed to interact with FANCE. PMID:9398857 we demonstrate the FAA and FAC bind each other and form a complex. Protein binding correlates with the functional activity of FAA and FAC, as patient-derived mutant FAC (L554P) fails to bind FAA.

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