FANCC is a noncatalytic component of the Fanconi anemia nuclear core complex that supports DNA interstrand cross-link repair and chromosome stability. It associates with FANCE and FANCF in a module coupled to the FANCL–UBE2T ubiquitination machinery, which modifies FANCD2–FANCI during repair. FANCC contributes to the assembly and function of this machinery, although its specific molecular step within the module remains unresolved. FANCC also has cytoplasmic functions, including context-dependent interactions with chaperone and PKR signaling systems and a role in mitochondrial quality control and limiting oxidative stress. Biallelic pathogenic variants cause Fanconi anemia complementation group C, characterized by bone-marrow failure, congenital abnormalities and increased cancer susceptibility.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0034599 cellular response to oxidative stress | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited oxidative-stress response is retained with independent target-specific support. Reason: The actual PTN000423656 IBD and target path are verified; the current mouse source is PMID:24483844. Its Fancc/Foxo3a double-mutant genetic/developmental findings are positive, but the detailed ROS, neurosphere and antioxidant-rescue experiments in the read main predominantly use Fancd2/Foxo3a mice; the inaccessible Fancc Supplementary Figure S1 is not claimed read. Independent PMID:27133164 directly tests immortalized human FANCC R548X patient fibroblasts with wild-type rescue: CCCP-induced mitochondrial ROS and abnormal mitochondrial accumulation are reduced by FANCC, with separate mouse macrophage experiments. Retain a real contextual stress-response role, not merely an assumed downstream consequence of DNA repair. No FANCC antioxidant-enzyme chemistry, universal tissue effect or new mitophagy annotation is inferred. The inherited STAT1 and reductase quotations remain context only, with their abstract-level access limits explicit. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000423656 SUPPORTS TRANSFER The exact human Q00597 558-residue target PTN002497666 is beneath PTN000423656 in the saved PANTHER v19 PTHR16798 tree/MSA, with all three source IBDs and no target-path NOT verified. The inherited response is biologically supported by positive mouse genetics and independently read human FANCC rescue experiments. Contextual non-core treatment does not imply a propagation failure; no donor-count or self-WITH objection is used. 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 | MODIFY | Summary: The verified inherited repair biology is more faithfully represented by interstrand cross-link repair. Reason: The actual source node and human target path are valid. Current mouse P50652 donor GOA traces the NER assertion to PMID:8704201: its complete main describes Fancc exon-9 disruption, MMC/DEB-induced chromosome radials in embryonic fibroblasts and MMC-dependent G2 accumulation in splenocytes. These are positive cross-link-response experiments, not an assay resolving excision of a lesion-containing oligonucleotide as specified by GO:0006289. Independent human FANCC complex/reconstitution and patient-cell complementation evidence supports participation in the ICL machinery (PMID:20347428, PMID:27986592 and PMID:27133164). Replace the target claim with GO:0036297 as a lateral lesion/role correction, not an ancestry refinement: ICL repair is not asserted to be a descendant of NER. This does not deny all possible FANCC participation in NER, invalidate the actual ancestral placement, or treat a single mouse donor as weak. The old review’s broad mechanistic dismissal is superseded; its inherited quotation remains untouched. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000423656 UNRESOLVED The exact human Q00597 558-residue target PTN002497666 is beneath PTN000423656 in the saved PANTHER v19 PTHR16798 tree/MSA, with all three source IBDs and no target-path NOT verified. Placement is verified, while the exact NER term is not resolved by the inspected donor lesion-response assays. Independent target evidence supports the lateral ICL replacement; no universal evolutionary loss or erroneous orthology is claimed. Proposed replacements: interstrand cross-link repair 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: Verified ancestral and human experimental evidence supports FANCC membership in the FA nuclear complex. Reason: The actual GO:0043240 IBD at PTN000423656 is on the exact human target path and cites human Q00597 as experimental descendant grounding; self-WITH is valid. Human HeLa FANCM immunopurification explicitly identifies FANCC (PMID:20347428, Results and Figure 1); FAAP20 co-immunoprecipitation also recovers FANCC (PMID:22266823, Figure 2). Human CEF reconstitution supplies complementary assembly evidence (PMID:27986592). Retain membership without assigning an isolated FANCC scaffold mechanism, one invariant complex stoichiometry, partner ligase chemistry or a C-specific DNA-contact activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000423656 SUPPORTS TRANSFER The exact human Q00597 558-residue target PTN002497666 is beneath PTN000423656 in the saved PANTHER v19 PTHR16798 tree/MSA, with all three source IBDs and no target-path NOT verified. Human Q00597 is a valid experimental self-WITH source, corroborated by independently read target-positive complex purification. 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: Human FANCC has an established nuclear pool. Reason: The actual UniProt Q00597 record lists a major nuclear and minor cytoplasmic form, and SL-0191 maps directly to GO:0005634. HPA independently supports nucleoplasm, while human HeLa nuclear-complex purification explicitly recovers FANCC (PMID:20347428, Results and Figure 1). Retain the encompassing nucleus term rather than treating nucleoplasm as its only possible subcompartment; nucleoplasm excludes chromosomes. The inherited PMID:9398857 quotation is retained with its abstract-level reading boundary. Neither the UniProt major/minor wording nor separate RefSeq models establishes distinct natural splice products. 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 | KEEP AS NON CORE | Summary: A genuine cytoplasmic FANCC pool is retained as a contextual location. Reason: The Q00597 subcellular-location record and actual SL-0086 map support cytoplasm. The positive PMID:9398857 abstract places unbound FAA/FAC mainly in cytoplasm and the complex in both cytoplasm and nucleus. Independently, PMID:27133164 measures FANCC-dependent mitochondrial quality control in human cells and conditional recruitment of tagged FANCC near damaged mitochondria. These distinguish nonnuclear pools from a universally soluble cytosol assignment. Retain the broad cytoplasmic location as non-core in this source context without calling the pool inactive, artifactual, or a distinct established natural isoform. 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 is a participating component of the machinery for interstrand cross-link repair. Reason: Actual InterPro IPR000686 spans the human Q00597 558-residue sequence and maps to GO:0036297 and GO:0043240. Human nuclear purification and CEF-containing reconstitution establish a physical contribution to the FA complex (PMID:20347428; PMID:27986592), and human FANCC knockout/WT rescue separates MMC-induced FANCD2 activation and survival from an independent mitophagy role (PMID:27133164, Figure 6). The inherited PMID:19965384 quotation concerns executed Xenopus ID2 depletion/add-back, not human FANCC incision. Retain structural participation without assigning FANCL/UBE2T ubiquitin transfer, nuclease cleavage or polymerase synthesis to FANCC. Whole-CEF experiments do not isolate a C-specific catalytic or adaptor activity. 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: The FANCC family mapping correctly assigns FA nuclear-complex membership. Reason: The current IPR000686 target match spans Q00597 residues 1–558 and its explicit GO mapping includes GO:0043240. Independent human nuclear-complex purification and CEF reconstitution corroborate membership (PMID:20347428; PMID:22266823; PMID:27986592). The inherited PMID:12649160 quotation remains intact. The abstract does not expose the complete experimental details; not every interaction in its model is independently demonstrated by the evidence inspected here. No partner catalytic activity is transferred. 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... | KEEP AS NON CORE | Summary: FANCC–FANCE association is supported independently of the inaccessible historical assay. Reason: The PMID:12649160 abstract reports FANCE-region binding to FANCC and loss of that interaction with FANCC L554P; complete operative Methods and Results were not recovered. Independent human-cell BioPlex data in PMID:33961781 identify FANCC bait recovering FANCE in HCT116 cells. Human CEF coexpression/purification in PMID:27986592 also supports their module association, without resolving a purified binary interface or retrospectively validating the old constructs. No verified FANCE-specific binding term was found; an adaptor replacement would require the additional bridging mechanism reassessed separately. The supported association is retained as non-core under the campaign binding exception; it does not by itself establish FANCC adaptor, enzyme-regulator or obligate heterodimer activity. 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... | UNDECIDED | Summary: The original FANCC–SMAD4 screen context remains access-limited. Reason: PMID:24412244 is the verified colorectal-cancer interaction-screen paper, but its operative main text and target interaction table were not recovered from the exact publisher route. The imported WITH identifies SMAD4; the abstract alone does not establish the target assay, controls or native-versus-mutant scope. DNA-binding-transcription-factor binding was considered, but no specific replacement or removal is justified without the operative target evidence. Positive curated attribution is retained as unresolved, not contradicted. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | MODIFY | Summary: Refine the directly recorded MEOX2 interaction to DNA-binding transcription factor binding. Reason: PMID:26871637 Table S2B, rows 104–105, records MEOX2 interactions with reference FANCC_1 and alternative FANCC_2. Table S2A maps these constructs to KU178051 and KU178052; the study clones are not added as natural UniProt products. The main Results and Experimental Procedures describe sequence-checked human ORFs tested by yeast two-hybrid with repeated pairwise testing. No FANCC-specific orthogonal PCA result was found in Table S2C. The literal source Q6FHY5 is a MEOX2 record with its homeobox DNA-binding region; the independently curated MEOX2 record P50222 establishes the DNA-binding transcription-factor class. GO:0140297 names this partner-specific binding without asserting that FANCC regulates transcription or that the two MEOX2 records have identical sequences. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex records FANCC bait recovering FANCE in HCT116 cells. Reason: The actual BioPlex HCT116 network table contains Q00597/FANCC–Q9HB96/FANCE at line 32947, and its directed-edge table identifies FANCC bait and FANCE prey at line 38136. The separately inspected 293T tables do not contain this pair; that release-specific absence is not evidence of biological nonbinding. PMID:33961781 Methods describe sequence-verified human ORFeome C-terminal FLAG–HA constructs, anti-HA affinity purification and mass-spectrometry scoring. This supports cellular coassociation rather than a purified binary interface, reciprocal capture, or exact current-product sequence proof. The supported association is retained as non-core under the campaign binding exception; it does not by itself establish FANCC adaptor, enzyme-regulator or obligate heterodimer activity. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | MODIFY | Summary: Refine the experimentally supported AKT1 association to protein kinase B binding. Reason: PMID:35512704 Data S1, Figure iiiA, directly displays FLAG-tagged FANCC recovered with GST-AKT1 in transfected HEK293T cells, with a wild-type AKT1 signal and a stronger E17K-mutant signal. The panel was visually inspected; no new densitometry is claimed. Table S3B row 10 separately records positive AKT1-E17K/FANCC validation. The paper’s main Methods distinguish tagged proximity, split-luciferase and pull-down assays; the semi-endogenous MCF7 panel does not show FANCC. GO:0043422 precisely names binding to protein kinase B/AKT, without assigning FANCC kinase activity, substrate status or an established native-cell DNA-repair mechanism. The unreadable Table S2 file and mutation annotations remain explicit source limits. Proposed replacements: protein kinase B binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:9596688 Molecular chaperone GRP94 binds to the Fanconi anemia group ... | KEEP AS NON CORE | Summary: FANCC associates with GRP94 in the reported yeast two-hybrid and coimmunoprecipitation assays. Reason: The complete cached primary abstract of PMID:9596688 explicitly reports FAC/FANCC–GRP94 yeast two-hybrid interaction and coimmunoprecipitation from transfected COS-1 cytosolic lysates and mouse liver extracts. Together with the curator's positive IPI attribution, this supports retaining the generic association as non-core under the campaign binding exception. The unresolved issue is the more specific GO:0051879 Hsp90 protein binding refinement, which remains deferred because complete Methods, target controls and Results were not recovered. This decision does not claim purified binary binding, FANCC chaperone activity or equivalence of the study splice-deletion construct to a natural product. 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: Human Protein Atlas supports a nucleoplasmic FANCC pool. Reason: The actual HPA ENSG00000158169 record assigns supported nucleoplasm with antibody HPA030771 in A-431 and U-251MG cells. Its 120-residue antigen exactly matches Q00597 residues 104–223. Selected merged images were inspected: A-431 shows nuclear green puncta; U-251MG has much weaker sparse nuclear signal. Retain the source-supported pool without upgrading antibody staining to chromatin binding, DNA-damage recruitment or exclusive localization. No U2OS image or separate RefSeq-protein localization is claimed. Supporting Evidence: GO_REF:0000052 |
| GO:0000785 chromatin | IDA PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr... | UNDECIDED | Summary: The inspected source establishes nuclear core membership but does not resolve FANCC chromatin association. Reason: PMID:22343915 main Figure 5H assays FANCA, FANCG, FAAP20 and H2A in the chromatin fraction. The newly recovered authentic supplement, Figure S1C, explicitly detects FANCC in human HeLa FAAP20 immunoprecipitates, while Figure S1B describes nuclear-extract purification. These are positive core-membership data, not an independently resolved FANCC chromatin fraction. The complete supplement text and S1 pixels were inspected. A legitimate complex-level projection remains possible; this is neither a claim that FANCC is absent from chromatin nor a confirmed wrong-gene citation. The exact evidence underlying the imported C-specific IDA remains unresolved. 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: FANCC participates in ICL repair as a component of the FA core machinery. Reason: This imported assertion is NAS. PMID:19965384 directly demonstrates Xenopus FANCI/FANCD2-dependent replication-coupled ICL repair and is pathway context, not a FANCC-specific perturbation. Independently inspected human FANCC-containing core purification (PMID:20347428) and human CEF reconstitution with BL100 and Xenopus ID2 (PMID:27986592) support FANCC participation through complex organization. The measured incision/TLS steps and FANCL ubiquitin-transfer chemistry are not reassigned to FANCC. 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: The authentic supplement explicitly corroborates FANCC core membership. Reason: PMID:22343915 Figure S1C displays FANCC in tagged FAAP20 immunoprecipitates from human HeLa cells, with vector control. The supplement Methods identify the FANCC constructs separately from natural products, while Figure S1B and the main Results describe nuclear-core purification. The imported NAS code is preserved; the inspected positive data support the membership claim without changing it to chromatin-specific residence or autonomous C adaptor activity. 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 | KEEP AS NON CORE | Summary: A cytosolic FANCC pool is retained in the PKR-response model. Reason: Reactome R-HSA-9835411 has actual input/output routes through FA-core:HSP70 complexes to human FANCC entity 420801, residues 1–558, whose own compartment is cytosol GO:0005829. The event emphasizes FANCC-dependent PKR inhibition. The actual PMID:15299030 abstract reports FANCA/FANCC/FANCG functional interactions in human bone-marrow and FA-C lymphoblast preparations, including PKR inhibition/rescue, but complete operative Methods were not recovered here. Retain this positive location as a contextual non-core facet, without assigning intrinsic kinase activity to FANCC, labeling cytosolic protein inactive, or equating all cytoplasmic pools with cytosol. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785126 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during core assembly. Reason: Reactome:R-HSA-6785126 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. FANCC is a direct input and a component of the assembled output. The event explicitly describes nucleoplasmic assembly before loading onto DNA. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785342 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during ID2 and UBE2T recruitment. Reason: Reactome:R-HSA-6785342 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. FANCC remains in the core-containing input and output. FANCL and the ID2 proteins have the specified recruitment roles; FANCC is not made the E2 enzyme. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785361 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during ID2 monoubiquitination. Reason: Reactome:R-HSA-6785361 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. The target occurs in input, output and the composite catalytic assembly. UBE2T and FANCL perform ubiquitin transfer; the route does not establish autonomous FANCC ligase chemistry. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785732 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during nuclease recruitment. Reason: Reactome:R-HSA-6785732 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. FANCC remains in input and output complexes; the newly recruited nucleases and docking proteins are distinct performers. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785986 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during ICL unhooking. Reason: Reactome:R-HSA-6785986 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. Input, output and composite-catalyst routes contain FANCC. The incision chemistry belongs to the named nucleases, not to every subunit of that assembly. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786155 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during POLN recruitment. Reason: Reactome:R-HSA-6786155 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. FANCC occurs in the core-containing input and output. POLN is the recruited DNA polymerase, not FANCC. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786166 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during POLN translesion synthesis. Reason: Reactome:R-HSA-6786166 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. FANCC is in input, core-complex output and a composite catalyst route; POLN performs synthesis. The event narrative distinguishes subsequent NER/HR steps from the FA-core location assertion. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786171 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during ID2 deubiquitination. Reason: Reactome:R-HSA-6786171 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. The FANCC-containing core is in the substrate complex and output. The separate USP1:WDR48 complex performs deubiquitination. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788385 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during ATR–ATRIP recruitment. Reason: Reactome:R-HSA-6788385 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. The target persists in input and output. Named RPA/FANCM/FAAP24/FANCL contacts do not establish a binary FANCC–ATRIP interface. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788392 | ACCEPT | Summary: Reactome places FANCC in nucleoplasm during ATR phosphorylation. Reason: Reactome:R-HSA-6788392 was traced through its actual participant links to human FANCC entity 419530, Q00597 residues 1–558, with its own GO:0005654 compartment. FANCC is in input, output and composite catalyst routes. ATR is the kinase and the named substrates are other components; kinase activity is not transferred to FANCC. Independent human HPA nucleoplasmic staining and HeLa nuclear-complex purification corroborate the compartment. These pathway contexts are not ten independent localization experiments, and membership does not confer all activities of their composite catalysts. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6806425 | ACCEPT | Summary: The TP53-expression event contains a nucleoplasmic FANCC protein output. Reason: Actual Reactome R-HSA-6806425 has FANCC gene DNA 6806593 as input and FANCC protein 419530, Q00597 residues 1–558 in nucleoplasm, as output; TP53-containing regulation is separate and no catalystActivity is assigned to FANCC. PMID:9063748 reports p53 binding/transactivation of the FANCC promoter in its accessible abstract, not FANCC performing transcription. Retain the modeled output location, independently supported by HPA; do not make FANCC a transcription regulator or claim this event is direct localization microscopy. |
| GO:0043240 Fanconi anaemia nuclear complex | IDA PMID:22266823 Regulation of Rev1 by the Fanconi anemia core complex. | ACCEPT | Summary: Human FANCC is recovered in the FAAP20-associated core complex. Reason: PMID:22266823 Results and Figure 2a explicitly show FANCC, FANCE and FANCA coimmunoprecipitating with tagged FAAP20 from human 293T cells. The separate in vitro translated direct-binding assay in Figure 2b tests FANCA–FAAP20, not FANCC–FAAP20. Accept core membership while preserving that distinction and avoiding transfer of FAAP20 ubiquitin/Rev1-binding activity. 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: FANCC is a constituent of the purified human nuclear FA core complex. Reason: PMID:20347428 Results and Figure 1C/E identify FANCC in FANCM/MHF-associated core immunoprecipitates from human HeLa nuclear extract. The source also resolves a separate smaller FANCM/MHF pool. This is positive FANCC complex-membership evidence; it does not assign FANCM DNA remodeling or MHF DNA binding to FANCC, nor make every FANCM complex a FANCC-containing complex. Supporting Evidence: |
| GO:0005829 cytosol | IDA PMID:9596688 Molecular chaperone GRP94 binds to the Fanconi anemia group ... | KEEP AS NON CORE | Summary: Retain the experimentally attributed cytosolic FANCC pool as a contextual non-core location. Reason: The actual PMID:9596688 abstract explicitly reports FAC/GRP94 coimmunoprecipitation from cytosolic, but not nuclear, lysates of transfected COS-1 cells, with separate mouse-liver and rat-cell experiments. That is positive compartment evidence for the imported cytosol IDA. Complete operative Methods and figures remain unavailable, so no new inference about fraction purity, endogenous human localization, a particular natural isoform, or an isolated chaperone mechanism is made. For the broad cytosol claim, the explicit positive abstract, the original curator attribution and the independently traced cytosolic Reactome PKR model are concordant. Retain the supported location as non-core while recording the narrower assay limits; the earlier UNDECIDED action conflated those limits with uncertainty about the location itself. 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: FANCC is present in the human nuclear FA core complex. Reason: The PMID:9398857 abstract reports FAA/FAC complex in nuclear and cytoplasmic fractions, although its complete operative original remains inaccessible. Independent actual human HeLa nuclear-extract purification in PMID:20347428 Figure 1C/E explicitly includes FANCC, and PMID:22343915 Figure S1C corroborates FANCC core association. These positive preparations support nuclear residence without assuming that all FANCC is exclusively nuclear or that nuclear extraction alone proves chromatin binding. 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 ... | KEEP AS NON CORE | Summary: Retain the reported cytoplasmic FANCC pool as contextual localization. Reason: The traceable statement in the PMID:9398857 abstract reports predominantly cytoplasmic unbound FAA/FAC and the complex in both nuclear and cytoplasmic fractions. Complete operative Methods and Results were not recovered, so the old fractionation and quantitative distribution are not claimed independently reproduced. The positive statement supports retaining this broad contextual pool, consistent with the separately retained non-core PMID:9596688 cytosol IDA; the detailed assay Methods for that study remain unavailable. No blanket assertion that cytoplasmic FANCC is inactive is retained. 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... | MODIFY | Summary: Refine broad DNA repair to the supported interstrand cross-link repair pathway. Reason: PMID:1574115 identifies the human group-C cDNA by functional complementation in its accessible abstract; the complete operative original was not recovered. Independent human FANCC-containing nuclear-complex purification in PMID:20347428 and human CEF reconstitution in PMID:27986592 place FANCC in the core machinery that promotes ID2 monoubiquitination. The latter uses human CEF/BL100 proteins with Xenopus ID2 and does not isolate C catalytic activity. PMID:19965384 directly tests replication-coupled ICL repair in Xenopus extracts, not human FANCC nuclease chemistry. Together these sources justify the typed DNA-repair descendant GO:0036297 as the specific established pathway role, without transferring incision or ubiquitin-transfer catalysis to FANCC. Proposed replacements: interstrand cross-link repair 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 contributes to assembly of the FA core module. Reason: The PMID:9398857 abstract links FAA/FAC association to functional complementation and reports loss of binding by FANCC L554P, but complete operative text was not recovered. Independent human CEF coexpression/purification in PMID:27986592 uses FANCC as a physical constituent of the FANCE/FANCF module associated with BL100. This supports participation in arranging and bonding core components, rather than merely being an external repair substrate. It does not establish that FANCC alone bridges the catalytic module to ID2; the inherited molecular-adaptor proposal is reassessed separately. No verified narrower FA-complex-assembly term is substituted. 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... | UNDECIDED | Summary: The inherited adaptor proposal is not yet resolved at the FANCC-specific mechanistic level. Reason: The inherited source and both quotation anchors are preserved. PMID:12649160 has only an accessible abstract here: it supports FANCC–FANCE binding, while the explicitly reported yeast three-hybrid bridge is mediated by FANCG. This does not prove the complete paper lacks another FANCC assay. Actual human CEF/BL100 reconstitution in PMID:27986592 tests a whole module and assigns the independently described ID2 interaction to FANCE; it does not establish the inherited claim that FANCC itself bridges FANCL/UBE2T to ID2. Current GO:0030674 explicitly directs stable protein-complex scaffold roles to GO:0140378. A scaffold alternative is plausible, but positive membership and whole-module activity do not yet isolate the C-specific hold-together mechanism. Official same-role FANCE/FANCF/FANCG comparator annotations and the fixed-main GO-CAM index were checked; absence of these exact functions is caution, not proof of a gap. No new molecular-function assertion is manufactured. UNDECIDED leaves the mechanism for targeted reassessment without deleting the inherited source or claiming FANCC lacks a structural role. 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. |
| GO:0005515 protein binding | IPI PMID:24412244 Charting the molecular links between driver and susceptibili... | UNDECIDED | Summary: The original FANCC–FBXW7 screen context remains access-limited. Reason: The verified PMID:24412244 abstract reports the screen globally, while the complete target table and operative Methods remain unavailable. The imported partner Q969H0 is FBXW7, an SCF substrate-recognition subunit; partner identity alone does not establish binding to a complete ubiquitin ligase, enzyme regulation or FANCC substrate status. The annotation is not removed or declared false because the target experiment cannot be inspected. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | UNDECIDED | Summary: The curated SMAD4 proximity record is positive, but its original target matrix remains unreadable. Reason: PMID:35512704 main Methods establish the human tagged BRET screen and its wild-type/mutant comparisons. Actual IntAct records EBI-63711113, EBI-63706663, EBI-63715006 and EBI-63702524 identify FANCC/SMAD4 BRET contexts with mutation-with-no-effect features; these are positive curated records, not evidence of mutant-only or absent wild-type binding. However, both preserved downloads of the primary Table S2 workbook lack a readable ZIP directory, and no target-specific SMAD4 panel was inspected. A transcription-factor-binding refinement is plausible but is not asserted from curated features alone. UNDECIDED records that target-source limit without rejecting the interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | UNDECIDED | Summary: The curated FBXW7 proximity record is positive, with an unresolved primary target-table boundary. Reason: Actual PMID:35512704 IntAct records EBI-63689535, EBI-63693940, EBI-63684551 and EBI-63698153 identify FANCC/FBXW7 BRET contexts with mutation-with-no-effect features. The main Methods were read, but the primary Table S2 target matrix could not be parsed from either preserved download. FBXW7 is the SCF substrate-recognition subunit; the record does not on its own demonstrate FANCC binding to the assembled ligase, ligase regulation or a direct enzymatic reaction. Retain the positive curator attribution as unresolved pending readable target measurements; no wrong-gene or no-binding claim is made. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which FANCC-specific interaction or conformational effect couples assembly of the human C–E–F module to productive FANCD2–FANCI monoubiquitination, and can it be separated from altered abundance or stability of FANCE, FANCF and the catalytic module?
Q: Which endogenous FANCC pools and partner interactions mediate mitochondrial quality control and ROS restraint, and to what extent can those functions be separated from nuclear cross-link repair without relying on patient truncations as substitutes for the normal protein?
Experiment: Reconstitute sequence-verified human C–E–F and the catalytic complex with wild-type FANCC, a FANCC omission and interface variants selected from independently tested contacts. Measure subunit abundance, solubility, folding and complex stoichiometry before comparing direct partner binding, human ID2 recruitment and FANCD2/FANCI monoubiquitination. Include matched partner-omission and FANCL/UBE2T catalytic controls, and test cellular rescue of cross-link sensitivity separately. Treat the chicken-derived residue-295 interface prediction as a testable hypothesis, not a verified human interaction defect.
Hypothesis: FANCC may support a specific assembly or conformational step distinct from direct substrate recognition by its partners; separating these effects could resolve its molecular role without assuming adaptor or ligase activity.
Experiment: Use endogenous tagging and independently validated FANCC antibodies with knockout controls in human fibroblasts and a second relevant cell type. Compare wild-type rescue and defined separation-of-function variants at matched near-endogenous levels. Measure mitophagic flux, mitochondrial ROS, viability and nuclear cross-link repair independently, with stimulus, autophagy-blockade and partner-perturbation controls. Distinguish genuine mitochondrial recruitment from soluble carryover, and distinguish pathway flux from steady-state mitochondrial mass. Keep the normal 558-residue protein separate from engineered fragments, patient alleles and transcript predictions.
Hypothesis: The mitochondrial/ROS function can be experimentally separable from nuclear repair, but its physical operating pool and dependence on Parkin or PKR may differ by cell type and stimulus.
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