FANCC

UniProt ID: Q00597
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

Fanconi anemia group C protein (FANCC) is a non-catalytic subunit of the multiprotein Fanconi anemia (FA) core complex, an E3 ubiquitin ligase that monoubiquitinates the FANCD2-FANCI heterodimer in response to DNA damage. Within the FA core complex FANCC together with FANCE and FANCF forms the substrate-recognition module that positions the FANCD2-FANCI substrate for monoubiquitination by the catalytic FANCL/UBE2T module. FANCC binds directly to FANCE, and its assembly with FANCA is required for integrity and function of the complex; the patient mutation L554P abolishes both interactions and complementing activity. Activated (monoubiquitinated) FANCD2-FANCI then coordinates replication-coupled DNA interstrand cross-link repair, homologous recombination and REV1-dependent translesion synthesis, protecting cells from cross-linking agents and maintaining chromosome stability; loss of FANCC causes Fanconi anemia (bone marrow failure, congenital malformations and cancer predisposition). FANCC exists as a predominantly nuclear form that acts on chromatin and a minor cytoplasmic form; the cytoplasmic pool associates with chaperones (e.g. GRP94/HSP90B1) and has additional, structurally separable roles in cytokine signaling (IFN-gamma/STAT1) and suppression of apoptosis via modulation of the protein kinase PKR (EIF2AK2), together with a proposed role in the cellular response to oxidative stress.

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.

Core Functions

Non-catalytic substrate-recognition subunit of the Fanconi anemia (FA) core complex E3 ubiquitin ligase; FANCC binds FANCE (and, via complex assembly, FANCA) to form, with FANCF, the module that recruits and positions the FANCD2-FANCI substrate for monoubiquitination, thereby contributing to the ubiquitin-ligase activity of the complex.

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:12649160
    A central region of FANCE was sufficient for FANCC binding. A Leu554Pro mutant of FANCC failed to interact with FANCE.
  • PMID:22266823
    the complex, an E3 ligase, monoubiquitinates the FANCD2/FANCI heterodimer
  • 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.

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:11063725
The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG.
PMID:12397061
The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC.
PMID:12649160
Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems.
PMID:1574115
Cloning of cDNAs for Fanconi's anaemia by functional complementation.
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:24412244
Charting the molecular links between driver and susceptibility genes in colorectal cancer.
PMID:26871637
Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35512704
Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
PMID:9787138
Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase.
PMID:9398857
The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex.
PMID:9596688
Molecular chaperone GRP94 binds to the Fanconi anemia group C protein and regulates its intracellular expression.
PMID:11520787
The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality.
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-6806425
TP53 stimulates FANCC expression
Reactome:R-HSA-9835411
FA core complex:HSP70s binds PKR

Suggested Questions for Experts

Q: Is FANCC's molecular role best captured as a molecular adaptor within the substrate-recognition module, and should GO provide a subunit-level term for FA core complex substrate recognition?

Suggested experts: D'Andrea AD, Wang W

Q: Are the cytokine-signaling (STAT1/PKR) and oxidative-stress roles of FANCC mechanistically independent of the FA core complex, and do they warrant separate curation as non-core functions?

Suggested experts: Bagby GC, Pang Q

Suggested Experiments

Experiment: Design structure-guided separation-of-function mutants of FANCC that disrupt FANCE/substrate binding without affecting overall complex assembly, and assay FANCD2-FANCI monoubiquitination and ICL sensitivity.

Hypothesis: FANCC's contribution to FANCD2-FANCI monoubiquitination is mediated by its adaptor/substrate-recognition role rather than by supporting overall complex integrity.

Type: structure-function mutagenesis

Experiment: Quantitatively reconstitute FANCD2-FANCI monoubiquitination in vitro with and without FANCC to measure its contribution to the complex's ubiquitin-ligase activity.

Hypothesis: FANCC is required for efficient E3-ligase activity of the reconstituted FA core complex.

Type: in vitro reconstitution / biochemistry

Deep Research

Affinage

(FANCC-deep-research-affinage.md)
Affinage mechanistic annotation for FANCC (human) Affinage Affinage (Claude Sonnet reading pass + Opus synthesis pass) 34 citations

Affinage mechanistic annotation for FANCC (human)

Current model (mechanistic narrative)

FANCC encodes a ~60-kDa protein with dual roles in genome maintenance and cytoprotection, originally defined as a Fanconi anemia gene required for cellular resistance to DNA interstrand cross-linking agents [PMID:8499901, PMID:7517562]. As part of a nuclear FA core complex, FANCC assembles with FANCA, FANCG, FANCF, and FANCE in a series of interdependent interactions: FANCA-FANCC binding PMID:9398857, FANCG-bridged complex formation PMID:10373536, FANCF incorporation PMID:11063725, and FANCE-mediated linkage of FANCC to the substrate FANCD2 PMID:16127171; phosphorylation-dependent nuclear accumulation of this complex defines a common pathway disrupted across multiple FA complementation groups PMID:9789045. This assembly is required for FANCD2 monoubiquitination, and its loss abrogates that modification, elevates spontaneous chromosomal breakage, and confers selective sensitivity to cross-linking agents PMID:16762635. Downstream, FANCC promotes homologous recombination and error-prone repair of abasic sites, suppresses sister chromatid exchange, and acts in concert with BLM helicase to maintain genome stability [PMID:15327776, PMID:15616572], operating in parallel pathways with BRCA2 and HELQ [PMID:16687415, PMID:24005041]. Independently of the core complex, cytoplasmic FANCC exerts anti-apoptotic functions essential for hematopoietic progenitor survival [PMID:8621788, PMID:8977247]: it binds Hsp70 to form a ternary complex that inhibits the pro-apoptotic kinase PKR [PMID:11500375, PMID:12397061], binds non-phosphorylated STAT1 to facilitate its docking and activation at the IFN-gamma receptor PMID:10848598, and attenuates NADPH cytochrome P450 reductase activity PMID:9787138. Patient-derived mutant FANCC (L554P) loses both core-complex (FANCA, cdc2) and signaling (STAT1) interactions [PMID:9398857, PMID:9242535, PMID:10848598].

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

  • molecular_activity: GO:0060090 molecular adaptor activity, GO:0098772 molecular function regulator activity, GO:0003677 DNA binding
  • localization: GO:0005829 cytosol, GO:0005634 nucleus
  • pathway (Reactome): R-HSA-73894 DNA Repair, R-HSA-5357801 Programmed Cell Death, R-HSA-162582 Signal Transduction, R-HSA-9612973 Autophagy, R-HSA-1474165 Reproduction
  • partners: FANCA, FANCG, FANCF, FANCE, HSPA1A, STAT1, EIF2AK2, POR
  • complexes: Fanconi anemia core complex (FANCA-FANCC-FANCE-FANCF-FANCG), FANCC-FANCE-FANCD2 ternary complex, FANCC-Hsp70-PKR ternary complex, FANCC-FANCE-FANCF anti-crossover subcomplex

Dated findings (citation-anchored)

Year Confidence Finding PMIDs Journal
1994 High The FACC polypeptide localizes predominantly to the cytoplasm, as determined by cell fractionation and immunofluorescence; it is a 60-kDa protein, and FA group C cell lines express full-length, truncated, or no detectable FACC polypeptide. Two FACC-related proteins (FRP-50 and FRP-150) were also co-immunoprecipitated. PMID:7517562 Proceedings of the National Academy of Sciences of the United States of America
1996 High Cytoplasmic localization of the FAC protein is essential for its functional activity: cytoplasmic isoforms of FAC corrected both the DNA cross-linking defect and enhanced cytotoxicity in FA group C cells, whereas a nucleus-targeted isoform did not correct these phenotypes. PMID:8621788 The Journal of clinical investigation
1997 High FAA (FANCA) and FAC (FANCC) proteins bind each other and form a complex. While unbound FAA and FAC are predominantly cytoplasmic, the FAA-FAC complex is found in both cytoplasm and nucleus. A patient-derived mutant FAC (L554P) fails to bind FAA. PMID:9398857 Nature genetics
1997 Medium The FAC protein coimmunoprecipitates with the cyclin-dependent kinase cdc2. FAC expression increases during S phase, peaks at G2/M transition, and declines during M phase. The L554P patient-derived mutant FAC fails to bind cdc2, and the cdc2-binding region maps to the carboxyl-terminal 50 amino acids of FAC. PMID:9242535 Blood
1997 Medium FA-C lymphoblasts treated with low-dose MMC exhibit prolonged G2/M arrest associated with sustained inactivation of the cyclin B1/cdc2 kinase complex (sustained cyclin B1 accumulation and cdc2 tyrosine phosphorylation), whereas FAC-corrected cells show only transient inactivation. This implicates FAC in a cross-link damage avoidance pathway that signals to the cyclin B/cdc2 kinase. PMID:9187128 Cancer research
1998 Medium FAC protein binds to NADPH cytochrome P450 reductase (RED) in COS-1 and murine liver cells. This interaction requires the amino-terminal region of FAC and the cytosolic FMN-binding domain of RED. FAC expression suppresses RED-mediated reduction of cytochrome c, indicating FAC attenuates RED enzymatic activity. PMID:9787138 Blood
1998 High Functional activity of FANCA requires both FAC binding and nuclear localization. Mutation/deletion of the FANCA NLS abolishes FAC binding and nuclear localization; wild-type FAC promotes nuclear accumulation of FAA, and FAA promotes nuclear accumulation of FAC. Mutant FAA forms that fail to bind FAC also fail to support nuclear FAC accumulation. PMID:9742112 Molecular and cellular biology
1998 Medium FAA and FAC protect against cross-linker cytotoxicity from different subcellular compartments: nuclear localization of FAA is necessary and sufficient to correct MMC sensitivity in FA-A cells, whereas cytoplasmic FAC is required for its activity. No interaction between FAA and FAC was detected either in vivo or in vitro in this study. PMID:9746759 Blood
1998 Medium The FAA/FAC protein complex undergoes nuclear accumulation in a phosphorylation-dependent manner. FA cells from complementation groups A, B, C, E, F, G, and H are all defective in FAA/FAC complex formation, FAA phosphorylation, and nuclear accumulation of the complex, defining a common FA signaling pathway. PMID:9789045 Proceedings of the National Academy of Sciences of the United States of America
1999 High FANCG/XRCC9 is required for binding of FANCA and FANCC proteins. FANCG is a component of the nuclear FANCA-FANCC complex. The amino-terminal region of FANCA is required for FANCG binding, FANCC binding, nuclear localization, and functional activity. Disruption of this tripartite complex results in the FA cellular phenotype. PMID:10373536 Molecular and cellular biology
1999 Medium Human alpha spectrin II (alphaSpIISigma) forms a nuclear complex with FANCA and FANCC. Levels of alphaSpIISigma are reduced in FA-A, FA-B, FA-C, and FA-D cells, suggesting FA proteins contribute to its stability/expression in the nucleus. PMID:10551855 The Journal of biological chemistry
2000 High FANCF forms a nuclear complex with FANCA, FANCC, and FANCG in human lymphoblasts. FANCF is predominantly nuclear. These interactions require each of the FA proteins (A, C, F, G) except FANCD. Loss of any single FA protein (except D) disrupts the nuclear complex. PMID:11063725 Human molecular genetics
2000 High FANCC binds STAT1 (preferentially non-phosphorylated STAT1) and facilitates its docking at the IFN-gamma receptor alpha chain, enabling STAT1 phosphorylation. GST-fusion FANCC, but not mutant FANCC (L554P), binds STAT1 in cell lysates. Loss of FANCC results in defective STAT1 docking at the IFN-gammaR, corrected by FANCC transduction. PMID:10848598 Molecular and cellular biology
2000 Medium FANCC protein expression is regulated posttranscriptionally in a cell cycle-dependent manner: FANCC protein is lowest at G1/S and highest in M phase, while mRNA levels are constant throughout the cell cycle. This regulation is proteasome-dependent and is encoded within the FANCC coding sequence. PMID:10845936 Blood
2001 High FANCC interacts with the molecular chaperone Hsp70 via the ATPase domain of Hsp70 and the central 320 residues of FANCC; both Hsp40 and ATP/ADP are required. This FANCC-Hsp70 interaction protects hematopoietic cells from IFN-gamma/TNF-alpha-induced cytotoxicity. Alanine mutations in the Hsp70-interacting domain of FANCC block both Hsp70 binding and cytoprotection. PMID:11500375 The EMBO journal
2001 Medium FANCA, FANCC, and FANCG proteins bind to DNA containing psoralen interstrand cross-links, as shown by DNA affinity chromatography from HeLa cell nuclear extracts. PMID:11401546 Biochemistry
2002 High FANCC inhibits PKR (double-stranded RNA-dependent protein kinase) activity both in vivo and in vitro; this requires a physical interaction between FANCC and Hsp70, but not interactions with other Fanconi proteins. FANCC, Hsp70, and PKR form a ternary complex in lymphoblasts and in yeast expressing PKR. FANCC can exert this anti-apoptotic function independently of the FA multiprotein complex. PMID:12397061 The Journal of biological chemistry
2002 High FANCE promotes nuclear accumulation of FANCC and is required for FANCA-FANCC complex formation, FANCD2 monoubiquitination, and FANCD2 nuclear foci formation. HA-tagged FANCE coimmunoprecipitates with FANCA, FANCC, and FANCG but not FANCD2 in normal cells. PMID:12239156 Blood
2004 High FANCC promotes homologous recombination (HR) repair and also facilitates error-prone repair of endogenously generated abasic sites (via translesion synthesis/mutagenic repair). Efficient repair of cross-links in DT40 cells requires combined functions of FANCC, translesion synthesis, and HR. Loss of FANCC elevates spontaneous sister chromatid exchange (SCE) approximately 2-fold. PMID:15327776 Molecular cell
2004 High FANCC deficiency in DT40 cells elevates spontaneous SCE ~2-fold, requiring XRCC3 (HR factor). FANCC loss combined with RAD18 loss (TLS) yields more SCE than either single mutant (non-epistatic). FANCC is functionally linked to BLM helicase: the fancc/blm double mutant has similar SCE to blm alone, and MMC-induced BLM nuclear foci formation is severely reduced in fancc or fancd2 cells. PMID:15616572 The EMBO journal
2005 High FANCC, FANCE, and FANCD2 form a ternary complex: FANCE mediates the interaction between FANCC and FANCD2. FANCE mutants that interact with FANCC but not FANCD2 abrogate FANCD2 monoubiquitination and fail to complement FA-E cells. FANCE also mediates the interaction between FANCC and FANCF within the core complex. PMID:16127171 The Journal of biological chemistry
2006 Medium FANCC disruption abrogates FANCD2 monoubiquitination, confirming impaired FA pathway function. FANCC-deficient cancer cells show increased G2/M arrest and clastogenic damage in response to DNA interstrand cross-linking agents, but not gemcitabine, etoposide, or hydrogen peroxide. FANCC disruption also increases spontaneous chromosomal breakage. PMID:16762635 Gastroenterology
2006 Medium FANCE nuclear accumulation depends specifically on FANCC: other FA proteins are not involved in FANCE nuclear localization. The FANCE region interacting with FANCC is distinct from the region binding FANCD2, supporting a model where FANCE recruits FANCD2 to the core complex independently of FANCC binding. PMID:16513431 DNA repair
2006 Medium Epistasis analysis in DT40 cells shows FANCC (FA core complex) and BRCA2 CTD are epistatic for X-ray sensitivity, but FANCC and BRCA2 CTD act in parallel pathways for interstrand cross-link repair. BRCA2-dependent Rad51 chromatin loading after MMC is not compromised by loss of FANCC or FANCD2. PMID:16687415 The Journal of biological chemistry
2009 Medium FANCC suppresses telomere sister chromatid exchange (T-SCE) specifically when telomeres are short: Fancc deficiency increases T-SCE incidence in mice crossed into a short-telomere background (Tert+/- or Tert-/-), but not in mice with long telomeres. Fancc deficiency also accelerates telomere attrition during high-turnover hematopoietic cell transplantation. PMID:20022886 Human molecular genetics
2013 Medium HELQ operates in parallel to (non-epistatic with) FANCC for suppression of spontaneous chromosome instability: Helq/Fancc double mutant mice show substantially worse phenotypes (micronuclei, 53BP1 nuclear bodies) than either single mutant. Unlike Fancc-/- cells, Helq mutant cells retain intact FANCD2 monoubiquitination and focus formation. PMID:24005041 Nucleic acids research
2014 Medium Combined loss of dormant replication origins (Mcm4chaos3) and FANCC results in synergistic increases in stalled/collapsed replication fork markers and genome instability beyond either single mutant, identifying an important functional overlap between dormant origins and the FA pathway in maintaining fork progression. PMID:24589582 Nucleic acids research
2020 Medium ZIKV downregulates FANCC (via suppression of transcription factor E2F4) to evade selective autophagy and enhance viral replication. FANCC is essential for selective autophagy and acts as a negative regulator of ZIKV replication; Fancc KO mice show increased ZIKV infection. PMID:33073500 EMBO reports
2022 Medium FANCC deficiency promotes microglial pyroptosis via the p38/NLRP3 pathway, leading to secondary neuronal apoptosis in spinal cord injury. Overexpression of FANCC suppresses microglial pyroptosis and neuronal apoptosis; knockdown worsens both outcomes. PMID:35659106 Cell & bioscience
2023 Medium The FANCC-FANCE-FANCF subcomplex is evolutionarily conserved from vertebrates to plants and functions as an anti-crossover factor during meiotic recombination. Loss of FANCC, FANCE, or FANCF partially rescues CO-defective mutants; FANCC/FANCE/FANCF mutations cause synthetic meiotic catastrophe with the pro-CO factor MUS81. PMID:36652992 Nucleic acids research
1996 Medium FAC protein expression suppresses apoptosis induced by growth factor withdrawal in hematopoietic factor-dependent progenitor cell lines (32D and MO7e), promoting increased viability rather than proliferation, consistent with an anti-apoptotic function analogous to Bcl-2. PMID:8977247 Blood
1996 Medium Antisense oligonucleotide-mediated repression of FACC gene expression in normal human bone marrow cells inhibits clonal growth of erythroid and granulocyte-macrophage progenitors in a sequence-specific fashion, establishing a direct role for FACC in hematopoietic progenitor cell growth/survival. PMID:7518843 The Journal of clinical investigation
2004 Medium Type I IFN-induced activation of STAT1, STAT3, and STAT5, as well as TYK2 and JAK1 phosphorylation, is impaired in FA-C cells bearing FANCC-inactivating mutations. This is accompanied by reduced Th1 (IFN-gamma-producing CD4+) differentiation in Fancc null mice. PMID:15356134 Journal of immunology
1993 Medium A leucine-to-proline substitution at codon 554 (L554P) completely abolishes FACC protein functional complementing activity, confirming that FACC encodes a ~60 kDa protein required for resistance to DNA cross-linking agents. PMID:8499901 Human molecular genetics

Citations

  • PMID:10373536
  • PMID:10551855
  • PMID:10845936
  • PMID:10848598
  • PMID:11063725
  • PMID:11401546
  • PMID:11500375
  • PMID:12239156
  • PMID:12397061
  • PMID:15327776
  • PMID:15356134
  • PMID:15616572
  • PMID:16127171
  • PMID:16513431
  • PMID:16687415
  • PMID:16762635
  • PMID:20022886
  • PMID:24005041
  • PMID:24589582
  • PMID:33073500
  • PMID:35659106
  • PMID:36652992
  • PMID:7517562
  • PMID:7518843
  • PMID:8499901
  • PMID:8621788
  • PMID:8977247
  • PMID:9187128
  • PMID:9242535
  • PMID:9398857
  • PMID:9742112
  • PMID:9746759
  • PMID:9787138
  • PMID:9789045

📚 Additional Documentation

Notes

(FANCC-notes.md)

FANCC (Q00597) — gene review notes

Identity

  • Human Fanconi anemia group C protein (FACC / FAC). UniProt Q00597, HGNC:3584, GeneID 2176, chr 9q22.32. 558 aa, ~63 kDa.
  • One of the FA "core complex" subunits. First FA gene cloned by functional complementation
    PMID:1574115.

Core biology — FA core complex subunit required for FANCD2-FANCI monoubiquitination / ICL repair

  • The FA core complex is a multisubunit E3 ubiquitin ligase; FANCC is a non-catalytic subunit of it.
    PMID:22266823.
  • FANCC is co-immunoprecipitated as an integral member of the core complex
    PMID:22266823.
  • The five-subunit nuclear complex (FANCA/C/E/F/G) is required for FANCD2 monoubiquitination
    PMID:12649160.
  • FANCC binds FANCE directly; the disease mutation L554P abolishes this
    PMID:12649160.
  • Structural placement (cryo-EM, not in GOA): FANCC-FANCE-FANCF constitute the substrate-recognition
    module of the FA core E3 ligase, present in a single copy, that positions the FANCD2-FANCI substrate
    for monoubiquitination by the FANCL RING/UBE2T module (Shakeel et al. 2019 Nature, PMID:31666700;
    deep-learning atomic model PMID:32939280; PDB 7KZP chain C = FANCC 1-558). This supports a
    molecular-adaptor / substrate-scaffold role and contribution to the complex's ubiquitin-ligase activity.
  • Downstream: monoubiquitinated FANCI-FANCD2 drives replication-coupled ICL repair in S phase
    [PMID:19965384 "A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex" ; "FANCI-FANCD2 is required for replication-coupled ICL repair in S phase."].

FANCC and translesion synthesis (TLS) — branch of the pathway

  • Genetic (DT40) epistasis links FANCC to REV1-mediated error-prone TLS; the FA core (not FANCD2) is
    needed for REV1 focus formation and point mutagenesis
    PMID:22266823
    PMID:22266823.

FA core complex assembly / integrity — FANCA-FANCC interaction

  • FANCA (FAA) and FANCC (FAC) bind each other; binding correlates with function and is lost in L554P
    PMID:9398857.
  • Unbound FAA/FAC are largely cytoplasmic; the assembled complex is both cytoplasmic and nuclear
    PMID:9398857.
  • FA core also present in a larger BLM-containing "BRAFT" super-complex
    PMID:12724401.
  • FAAP20 is an integral core-complex protein needed for DNA-damage-induced chromatin loading of the core
    [PMID:22343915 "We show that FAAP20 is an integral component of the FA nuclear core complex." ; "The FAAP20-UBZ domain is not required for interaction with FANCA, but is required for DNA-damage-induced chromatin loading of FANCA and the functional integrity of the FA pathway."].

Non-core / additional proposed roles (context-specific, separable from ICL-repair function)

  • Cytoplasmic chaperone GRP94/HSP90B1 binds FANCC and regulates its steady-state level; interaction is
    cytosolic, not nuclear
    [PMID:9596688 "Binding was confirmed by coimmunoprecipitation of FAC and GRP94 from cytosolic, but not nuclear, lysates" ; "Ribozyme-mediated inactivation of GRP94 ... led to significantly reduced levels of immunoreactive FAC and concomitant hypersensitivity to mitomycin C"]. This is a stability/localization interaction, not a distinct MF.
  • Cytokine signaling / apoptosis: FANCC promotes IFN-gamma-induced STAT1 activation and suppresses
    cytokine-induced apoptosis via modulation of PKR (EIF2AK2). These functions are STRUCTURALLY SEPARABLE
    from the cross-linker-resistance/FANCD2 function
    PMID:11520787
    PMID:11520787.
    => Treat oxidative-stress/redox and cytokine/apoptosis roles as NON-CORE.

Localization summary

  • UniProt: Nucleus + Cytoplasm; "The major form is nuclear. The minor form is cytoplasmic." Assembled
    FA core acts in the nucleoplasm/on chromatin; cytosolic pool associates with chaperones (GRP94) and a
    PKR/HSP70 complex (Reactome R-HSA-9835411). Nucleoplasm (HPA IDA) and chromatin (ComplexPortal IDA)
    are well supported.

Annotation-review decisions (summary)

  • GO:0043240 Fanconi anaemia nuclear complex (part_of; IBA/IEA/NAS/IDA x5): ACCEPT — CORE.
  • GO:0036297 interstrand cross-link repair (IEA, NAS): ACCEPT — CORE.
  • GO:0006281 DNA repair (TAS): ACCEPT (general parent, correct).
  • GO:0065003 protein-containing complex assembly (TAS): ACCEPT (FANCC needed for FA core assembly/integrity).
  • GO:0034599 cellular response to oxidative stress (IBA): KEEP_AS_NON_CORE (mouse-driven phylogenetic;
    redox role real but peripheral, separable from ICL repair).
  • GO:0006289 nucleotide-excision repair (IBA): MARK_AS_OVER_ANNOTATED — FANCC is not a canonical NER
    factor; its process is ICL repair / TLS regulation. Over-propagated IBA.
  • GO:0005515 protein binding (IPI x6): MARK_AS_OVER_ANNOTATED — uninformative MF; specific partners
    (FANCE, GRP94, SMAD4, FBXW7, MEOX2, AKT1) are largely HT/network or captured better by complex terms.
  • Locations nucleus/cytoplasm/nucleoplasm/cytosol/chromatin: ACCEPT (all supported).

References not in GOA but used for context (notes only; not cited as supporting_text)

  • PMID:31666700 Shakeel et al., Structure of the FA monoubiquitin ligase complex, Nature 2019.
  • PMID:32939280 Deep-learning atomic structure of FA core complex (PDB 7KZP), 2020.

📄 View Raw YAML

 
id: Q00597
gene_symbol: FANCC
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Fanconi anemia group C protein (FANCC) is a non-catalytic subunit of the multiprotein Fanconi
  anemia (FA) core complex, an E3 ubiquitin ligase that monoubiquitinates the FANCD2-FANCI heterodimer
  in response to DNA damage. Within the FA core complex FANCC together with FANCE and FANCF forms the
  substrate-recognition module that positions the FANCD2-FANCI substrate for monoubiquitination by the
  catalytic FANCL/UBE2T module. FANCC binds directly to FANCE, and its assembly with FANCA is required
  for integrity and function of the complex; the patient mutation L554P abolishes both interactions and
  complementing activity. Activated (monoubiquitinated) FANCD2-FANCI then coordinates replication-coupled
  DNA interstrand cross-link repair, homologous recombination and REV1-dependent translesion synthesis,
  protecting cells from cross-linking agents and maintaining chromosome stability; loss of FANCC causes
  Fanconi anemia (bone marrow failure, congenital malformations and cancer predisposition). FANCC exists
  as a predominantly nuclear form that acts on chromatin and a minor cytoplasmic form; the cytoplasmic
  pool associates with chaperones (e.g. GRP94/HSP90B1) and has additional, structurally separable roles
  in cytokine signaling (IFN-gamma/STAT1) and suppression of apoptosis via modulation of the protein kinase
  PKR (EIF2AK2), together with a proposed role in the cellular response to oxidative stress.
existing_annotations:
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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).
    supported_by:
    - reference_id: PMID:11520787
      supporting_text: 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.
    - reference_id: PMID:9787138
      supporting_text: 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.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      failure_modes:
      - ROLE_CONFLATION
      source_entities:
      - source_id: PANTHER:PTN000423656
        source_label: FANCC family node
        source_status: SUPPORTS_TRANSFER
        comment: Redox/oxidative-stress phenotype supported mainly by mouse Fancc (MGI:95480) knockouts;
          a real but non-core, downstream role.
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN000423656
        source_label: FANCC family node
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: 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.
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12649160
      supporting_text: The FANCA, FANCC, FANCE, FANCF, and FANCG proteins form a nuclear complex required
        for the monoubiquination of the FANCD2 protein.
    - reference_id: PMID:22266823
      supporting_text: Flag-tagged FAAP20 co-immunoprecipitated with FANCA, FANCE, and FANCC, indicating
        that FAAP20 associates with the FA core complex
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Consistent with subcellular-location mapping and with experimental data showing the assembled
      FAA-FAC complex is abundant in the nucleus.
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: the FAA-FAC complex 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: 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.
    action: ACCEPT
    reason: Supported by multiple localization studies; UniProt lists Cytoplasm as a location (the minor
      form is cytoplasmic).
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: Although unbound FAA and FAC localize predominantly to the cytoplasm, the FAA-FAC
        complex is found in similar abundance in both cytoplasm and nucleus.
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Well supported; ICL repair is the defining process of the FA pathway and FANCC deficiency
      causes cross-linker hypersensitivity.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation
        of the FANCI-FANCD2 complex
    - reference_id: PMID:22266823
      supporting_text: the FA proteins cooperate in a DNA damage response (DDR) pathway required for DNA
        interstrand crosslink repair
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: InterPro-based inference that FANCC is part of the FA nuclear complex; consistent with the
      FANCC domain signature and with experimental data.
    action: ACCEPT
    reason: Correct and core; redundant with the experimental part_of annotations but appropriately captures
      complex membership.
    supported_by:
    - reference_id: PMID:12649160
      supporting_text: The FANCA, FANCC, FANCE, FANCF, and FANCG proteins form a nuclear complex required
        for the monoubiquination of the FANCD2 protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12649160
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:12649160
      supporting_text: A central region of FANCE was sufficient for FANCC binding. A Leu554Pro mutant
        of FANCC failed to interact with FANCE.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24412244
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term protein binding is uninformative; these are large-scale network interactions of low
      specificity for FANCC function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: High-throughput two-hybrid interaction (WITH MEOX2 Q6FHY5) from an alternative-splicing interactome
      map. Uninformative for FANCC's core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative GO term captured by a large-scale interactome screen; no evidence this interaction
      is relevant to FANCC's ICL-repair role.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Affinity-purification (BioPlex) interaction (WITH FANCE Q9HB96). Recovers the genuine FANCC-FANCE
      core-complex partnership but via an uninformative GO term.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35512704
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Large-scale screen interactions with an uninformative GO term; low specificity for FANCC biology.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9596688
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:9596688
      supporting_text: Binding was confirmed by coimmunoprecipitation of FAC and GRP94 from cytosolic,
        but not nuclear, lysates
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (HPA) localizes FANCC to the nucleoplasm, consistent with the nuclear
      site of FA core complex action.
    action: ACCEPT
    reason: Direct experimental localization; consistent with the nuclear FA-pathway function.
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:22343915
  qualifier: located_in
  review:
    summary: The FA core complex undergoes DNA-damage-induced chromatin loading; FANCC is annotated to
      chromatin as a complex member (ComplexPortal IDA).
    action: ACCEPT
    reason: Supported by evidence that core-complex chromatin loading is required for FA-pathway function;
      FANCC acts on chromatin as part of the complex.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: is required for DNA-damage-induced chromatin loading of FANCA and the functional
        integrity of the FA pathway.
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: NAS
  original_reference_id: PMID:19965384
  qualifier: involved_in
  review:
    summary: 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.
    action: ACCEPT
    reason: Core process for FANCC; the FA pathway is required for replication-coupled ICL repair.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi
        anemia pathway is compromised.
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: NAS
  original_reference_id: PMID:22343915
  qualifier: part_of
  review:
    summary: Author statement that FANCC is part of the FA nuclear core complex, whose integrity is required
      for the FA-BRCA DNA repair pathway.
    action: ACCEPT
    reason: Core complex membership, consistent with experimental co-purification.
    supported_by:
    - reference_id: PMID:22343915
      supporting_text: We show that FAAP20 is an integral component of the FA nuclear core complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835411
  qualifier: located_in
  review:
    summary: Reactome localizes a cytosolic FA core complex:HSP70:PKR assembly. Consistent with the documented
      minor cytoplasmic form of FANCC and its cytosolic PKR/HSP70 interactions.
    action: ACCEPT
    reason: Supported by the well-established cytoplasmic pool of FANCC; a valid, non-core location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785126
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC as the FA core complex assembles at ICLs.
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785342
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series.
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785361
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC (monoubiquitination of FANCD2-FANCI step).
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series.
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series.
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786155
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series.
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786166
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series.
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786171
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC (FANCD2 deubiquitination step context).
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788385
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series.
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788392
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC within the FA ICL-repair reaction series.
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6806425
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for FANCC (TP53 stimulates FANCC expression context).
    action: ACCEPT
    reason: Consistent with nuclear action of the FA core complex.
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:22266823
  qualifier: part_of
  review:
    summary: Direct experimental identification of FANCC in the FA core complex (co-immunoprecipitation
      with FANCA and FANCE). Core complex membership.
    action: ACCEPT
    reason: Direct experimental evidence for FANCC as an integral FA core complex subunit.
    supported_by:
    - reference_id: PMID:22266823
      supporting_text: Flag-tagged FAAP20 co-immunoprecipitated with FANCA, FANCE, and FANCC, indicating
        that FAAP20 associates with the FA core complex
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:20347428
  qualifier: part_of
  review:
    summary: 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.
    action: ACCEPT
    reason: Direct evidence supporting FANCC as a core complex subunit; do not overrule the experimental
      curation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:9596688
  qualifier: located_in
  review:
    summary: FANCC (FAC) was directly detected in cytosolic lysates by co-immunoprecipitation with the
      chaperone GRP94, consistent with a cytoplasmic pool of FANCC.
    action: ACCEPT
    reason: Direct experimental localization to the cytosol; supports the documented minor cytoplasmic
      form.
    supported_by:
    - reference_id: PMID:9596688
      supporting_text: Binding was confirmed by coimmunoprecipitation of FAC and GRP94 from cytosolic,
        but not nuclear, lysates
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:9398857
  qualifier: located_in
  review:
    summary: The assembled FAA-FAC (FANCA-FANCC) complex is found abundantly in the nucleus, supporting
      nuclear localization.
    action: ACCEPT
    reason: Supported by direct study of the FAA-FAC nuclear complex.
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: the FAA-FAC complex 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 FANCC (and FANCA) localize predominantly to the cytoplasm; the cytoplasmic form is
      well documented.
    action: ACCEPT
    reason: Supported by direct localization data on the FAA/FAC proteins.
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: Although unbound FAA and FAC localize predominantly to the cytoplasm
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: TAS
  original_reference_id: PMID:1574115
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Correct high-level process; retained as a valid general parent alongside the more specific
      ICL-repair annotation.
    supported_by:
    - reference_id: PMID:1574115
      supporting_text: Cloning of cDNAs for Fanconi's anaemia by functional complementation.
- term:
    id: GO:0065003
    label: protein-containing complex assembly
  evidence_type: TAS
  original_reference_id: PMID:9398857
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9398857
      supporting_text: 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.
    - reference_id: PMID:11063725
      supporting_text: This implies that each of the FA proteins, except FANCD, is required for these complexes
        to form.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IPI
  original_reference_id: PMID:12649160
  qualifier: enables
  review:
    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.'
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:12649160
      supporting_text: A central region of FANCE was sufficient for FANCC binding. A Leu554Pro mutant
        of FANCC failed to interact with FANCE.
    - reference_id: PMID:9398857
      supporting_text: 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.
core_functions:
- description: Non-catalytic substrate-recognition subunit of the Fanconi anemia (FA) core complex E3
    ubiquitin ligase; FANCC binds FANCE (and, via complex assembly, FANCA) to form, with FANCF, the module
    that recruits and positions the FANCD2-FANCI substrate for monoubiquitination, thereby contributing
    to the ubiquitin-ligase activity of the complex.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  contributes_to_molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  directly_involved_in:
  - id: GO:0036297
    label: interstrand cross-link repair
  - id: GO:0065003
    label: protein-containing complex assembly
  locations:
  - id: GO:0005654
    label: nucleoplasm
  - id: GO:0000785
    label: chromatin
  in_complex:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  supported_by:
  - reference_id: PMID:12649160
    supporting_text: A central region of FANCE was sufficient for FANCC binding. A Leu554Pro mutant of
      FANCC failed to interact with FANCE.
  - reference_id: PMID:22266823
    supporting_text: the complex, an E3 ligase, monoubiquitinates the FANCD2/FANCI heterodimer
  - reference_id: PMID:9398857
    supporting_text: 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.
proposed_new_terms: []
suggested_questions:
- question: Is FANCC's molecular role best captured as a molecular adaptor within the substrate-recognition
    module, and should GO provide a subunit-level term for FA core complex substrate recognition?
  experts:
  - D'Andrea AD
  - Wang W
- question: Are the cytokine-signaling (STAT1/PKR) and oxidative-stress roles of FANCC mechanistically
    independent of the FA core complex, and do they warrant separate curation as non-core functions?
  experts:
  - Bagby GC
  - Pang Q
suggested_experiments:
- hypothesis: FANCC's contribution to FANCD2-FANCI monoubiquitination is mediated by its adaptor/substrate-recognition
    role rather than by supporting overall complex integrity.
  description: Design structure-guided separation-of-function mutants of FANCC that disrupt FANCE/substrate
    binding without affecting overall complex assembly, and assay FANCD2-FANCI monoubiquitination and
    ICL sensitivity.
  experiment_type: structure-function mutagenesis
- hypothesis: FANCC is required for efficient E3-ligase activity of the reconstituted FA core complex.
  description: Quantitatively reconstitute FANCD2-FANCI monoubiquitination in vitro with and without FANCC
    to measure its contribution to the complex's ubiquitin-ligase activity.
  experiment_type: in vitro reconstitution / biochemistry
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:11063725
  title: The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (abstract cached; via Affinage). Shows FANCF complexes with FANCA, FANCC
      and FANCG in the nucleus and that loss of any FA protein except FANCD disrupts these complexes,
      documenting interdependent FA core complex assembly. Added as additional support for the protein-containing
      complex assembly (GO:0065003) annotation.
- id: PMID:12397061
  title: The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent
    protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (abstract cached; via Affinage). Establishes the FANCC-Hsp70-PKR ternary
      complex and shows FANCC inhibits PKR kinase activity to support hematopoietic cell survival. Crucially,
      it states this anti-apoptotic function is structurally separable from and does not require the FA
      multimeric complex, corroborating (not overturning) the review's treatment of the PKR/apoptosis-signaling
      role as non-core. Not annotated to a GOA term for FANCC; cited as background for the non-core signaling
      role noted in the description.
- 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: PubMed-verified. Maps the direct FANCC-FANCE interaction (a central region of FANCE
      binds FANCC; L554P abolishes it) and establishes the FANCA/C/E/F/G nuclear complex required for
      FANCD2 monoubiquitination. Directly supports FANCC's core adaptor/complex role.
- id: PMID:1574115
  title: Cloning of cDNAs for Fanconi's anaemia by functional complementation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Original cloning of FANCC (FACC) by functional complementation, establishing
      involvement in FA and DNA repair.
- id: PMID:19965384
  title: The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Establishes that FANCI-FANCD2 monoubiquitination drives replication-coupled
      ICL repair; supports the pathway-level process for FANCC though it focuses on the FANCD2-FANCI step
      rather than FANCC directly.
- id: PMID:20347428
  title: A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability.
  findings: []
- id: PMID:22266823
  title: Regulation of Rev1 by the Fanconi anemia core complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (full text cached). Confirms FANCC as an integral FA core complex subunit
      (co-IP with FANCA/FANCE), the complex as an E3 ligase monoubiquitinating FANCD2-FANCI, and the FANCC-REV1
      TLS epistasis.
- 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: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Characterizes FAAP20 as an FA core-complex protein and shows the core
      complex is loaded onto chromatin in a damage-induced manner; supports FANCC chromatin and complex
      annotations.
- id: PMID:24412244
  title: Charting the molecular links between driver and susceptibility genes in colorectal cancer.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Source of high-throughput/network interactions (SMAD4, FBXW7); uninformative
      protein binding IPI, low specificity for FANCC function.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. High-throughput two-hybrid interactome (MEOX2 interaction); uninformative
      for FANCC's core function.
- 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: PubMed-verified (BioPlex). Recovers the genuine FANCC-FANCE interaction but via an uninformative
      protein binding IPI; complex membership is better captured elsewhere.
- id: PMID:35512704
  title: Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Large-scale neo-PPI screen (AKT1, SMAD4, FBXW7); uninformative GO term,
      low specificity for canonical FANCC biology.
- id: PMID:9787138
  title: Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the
    FAC protein with NADPH cytochrome P450 reductase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (abstract cached; via Affinage). FANCC (FAC) binds and attenuates NADPH
      cytochrome P450 reductase (RED), regulating a microsomal detoxification/redox pathway. This is the
      primary direct evidence for FANCC's redox-regulatory/detoxification role and is added as additional
      support for the non-core cellular response to oxidative stress (GO:0034599) annotation, whose prior
      supporting_text cited only a STAT1 study.
- 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: PubMed-verified. Demonstrates direct FANCA(FAA)-FANCC(FAC) binding required for the
      functional nuclear complex (lost in L554P) and defines nuclear/cytoplasmic distribution.
- id: PMID:9596688
  title: Molecular chaperone GRP94 binds to the Fanconi anemia group C protein and regulates its intracellular
    expression.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Establishes cytosolic FANCC-GRP94/HSP90B1 interaction regulating FANCC
      abundance; supports the cytosolic location but represents a peripheral/stability role.
- id: PMID:11520787
  title: 'The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (abstract cached). Shows FANCC's STAT1-activation/anti-apoptotic (PKR)
      functions are structurally separable from its cross-linker-resistance/FANCD2-activation function,
      supporting treatment of the signaling/stress roles as non-core.
- id: Reactome:R-HSA-6785126
  title: FA core complex assembles at DNA interstrand crosslinks (ICLs)
  findings: []
- id: Reactome:R-HSA-6785342
  title: FANCD2:FANCI complex and UBE2T bind ICL-DNA associated with the FA core complex
  findings: []
- id: Reactome:R-HSA-6785361
  title: Monoubiquitination of FANCD2:FANCI
  findings: []
- id: Reactome:R-HSA-6785732
  title: DNA nucleases bind monoubiquitinated ID2 complex
  findings: []
- id: Reactome:R-HSA-6785986
  title: DNA nucleases unhook the interstrand crosslink (ICL)
  findings: []
- id: Reactome:R-HSA-6786155
  title: POLN binds ICL-DNA
  findings: []
- id: Reactome:R-HSA-6786166
  title: Translesion synthesis across unhooked ICL by POLN
  findings: []
- id: Reactome:R-HSA-6786171
  title: FANCD2 deubiquitination by USP1:WDR48
  findings: []
- id: Reactome:R-HSA-6788385
  title: The complex of ATR and ATRIP is recruited to ICL-DNA
  findings: []
- id: Reactome:R-HSA-6788392
  title: ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA
  findings: []
- id: Reactome:R-HSA-6806425
  title: TP53 stimulates FANCC expression
  findings: []
- id: Reactome:R-HSA-9835411
  title: FA core complex:HSP70s binds PKR
  findings: []