FANCF is a subunit of the Fanconi anemia (FA) nuclear core complex, a multisubunit ubiquitin ligase that also contains FANCA, FANCB, FANCC, FANCE, FANCG, FANCL (the RING E3), FANCM and associated FAAP proteins. The core complex is activated by DNA damage, particularly DNA interstrand cross-links (ICLs) and replication stress, and its essential output is monoubiquitination of the FANCD2-FANCI (ID2) heterodimer. Monoubiquitinated ID2 is loaded onto chromatin near the lesion and directs the downstream steps of replication- coupled ICL repair (nucleolytic unhooking, translesion synthesis and homologous recombination), thereby maintaining chromosome stability. FANCF has no catalytic activity or recognizable sequence motif; its C-terminal domain adopts a HEAT/ARM-like helical-repeat fold and it acts as a flexible molecular adaptor/scaffold that bridges the FANCA:FANCG and FANCC:FANCE subcomplexes, so it is required for assembly and stability of the intact core complex and hence for FANCD2 monoubiquitination. FANCF is predominantly nuclear/nucleoplasmic and associates with chromatin upon DNA damage. Biallelic loss-of-function of FANCF causes Fanconi anemia complementation group F, with bone marrow failure, congenital malformations, cancer predisposition and cellular hypersensitivity to cross-linking agents.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006974 DNA damage response | IBA GO_REF:0000033 | ACCEPT | Summary: FANCF, as a subunit of the FA core complex, participates in the cellular response to DNA damage (ICLs and replication stress). Correct but broad; the specific process is interstrand cross-link repair. Reason: Well supported by phylogenetic inference and by direct evidence that the FA core complex is activated by DNA damage to monoubiquitinate FANCD2-FANCI. A valid parent term; retained as a general process alongside the more specific ICL repair annotation. Supporting Evidence: PMID:17082180 At least eight FA proteins (FANCA, B, C, E, F, G, L, and M) form a nuclear core complex required for monoubiquitination of a downstream protein, FANCD2. PMID:21915857 they showed an aberrant response to DNA cross-linking agents as manifested by G(2) arrest, chromosomal aberrations, reduced survival, and an inability to monoubiquitinate FANCD2. |
| GO:0043240 Fanconi anaemia nuclear complex | IBA GO_REF:0000033 | ACCEPT | Summary: FANCF is a bona fide subunit of the Fanconi anemia nuclear (core) complex. This is its core cellular-component annotation. Reason: Directly demonstrated: FANCF complexes with FANCA, FANCC and FANCG in the nucleus, and is a stable component of the eight-subunit FA core complex resolved by cryo-EM. Phylogenetic (IBA) call agrees with experimental data. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: FANCF localizes predominantly to the nucleus, consistent with its role in the nuclear FA core complex. Reason: UniProt subcellular-location mapping agrees with experimental immunofluorescence/fractionation showing predominant nuclear localization. Broad but correct (the more granular nucleoplasm term is also annotated). Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0036297 interstrand cross-link repair | IEA GO_REF:0000002 | ACCEPT | Summary: FANCF is required for the FA pathway that repairs DNA interstrand cross-links. Core biological process. Reason: The InterPro2GO mapping (FANCF family IPR035428 to ICL repair) is biologically correct: the FA core complex, of which FANCF is an essential adaptor subunit, drives FANCD2 monoubiquitination that is required for replication-coupled ICL repair. Supporting Evidence: PMID:19965384 FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. |
| GO:0043240 Fanconi anaemia nuclear complex | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (ARBA/InterPro) call that FANCF is part of the FA nuclear complex; duplicates the experimentally supported membership annotation. Reason: Consistent with experimental and phylogenetic evidence for FA core complex membership. Redundant with the IBA/IDA/NAS annotations to the same term but not incorrect. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG. |
| GO:0005515 protein binding | IPI PMID:11063725 The Fanconi anemia protein FANCF forms a nuclear complex wit... | MODIFY | Summary: IPI capturing FANCF interactions with FANCA (O15360) and FANCG (O15287), the core-complex partners it bridges. 'Protein binding' is uninformative; the underlying function is molecular adaptor/scaffold activity. Reason: These interactions are exactly the adaptor function of FANCF: it bridges the FANCA:FANCG and FANCC:FANCE subcomplexes to assemble the core complex. Replace the uninformative 'protein binding' with protein-macromolecule adaptor activity (GO:0030674), which captures the actual molecular function. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG. PMID:17082180 The human FANCF protein reportedly functions as a molecular adaptor within the FA nuclear complex, bridging between the subcomplexes A:G and C:E. PMID:15262960 Our data demonstrate that FANCF acts as a flexible adaptor protein that plays a key role in the proper assembly of the FA core complex. |
| GO:0005515 protein binding | IPI PMID:12649160 Fanconi anemia protein complex: mapping protein interactions... | MODIFY | Summary: Yeast two/three-hybrid mapping of the FANCF-FANCG (and FANCA) contacts. As with the other core-complex interaction, the informative molecular function is adaptor activity, not the generic 'protein binding'. Reason: The mapped FANCF/FANCG contact and FANCG-mediated bridging of FANCA to FANCF are the physical basis of FANCF's scaffolding role. Modify to protein-macromolecule adaptor activity (GO:0030674). Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:12649160 FANCG was shown to interact with both the amino-terminus of FANCA and the carboxyl-terminal region of FANCF. PMID:12649160 FANCG was able to mediate interaction between FANCA and FANCF |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: High-throughput binary interactome (HuRI) Y2H hit between FANCF and TCP11 (Q8WWU5-7). Real recorded interaction but uninformative and with no established relevance to FANCF function. Reason: A systematic all-by-all Y2H screen; the interaction is not corroborated by focused studies and TCP11 has no known role in the FA pathway. Retain as a documented interaction but it is non-core and 'protein binding' carries no functional information. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Y2H hit between FANCF and HTT (huntingtin, P42858) from a neurodegeneration-focused interactome screen. Real recorded interaction but uninformative and of no established relevance to FANCF function. Reason: Large-scale screen aimed at neurodegenerative-disease proteins; the FANCF- HTT interaction is not supported by focused FA-pathway studies. Retain as a documented interaction but mark non-core; 'protein binding' is uninformative as a molecular function. Supporting Evidence: PMID:32814053 systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) localizes FANCF to the nucleoplasm, consistent with its role in the nuclear FA core complex. Reason: Direct immunofluorescence evidence agrees with the predominant nuclear localization reported for endogenous FANCF and the core complex. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0000785 chromatin | IDA PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr... | ACCEPT | Summary: The FA core complex (including FANCF) is loaded onto chromatin in response to DNA damage; ComplexPortal-curated chromatin localization. Reason: Consistent with DNA-damage-induced chromatin recruitment of the FA core complex, which is required for functional integrity of the FA-BRCA pathway. Experimental IDA assigned by ComplexPortal for the complex FANCF belongs to. 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: FANCF, via the FA core complex and FANCD2-FANCI monoubiquitination, contributes to replication-dependent DNA interstrand cross-link repair. Reason: The cited work establishes that the FA pathway (FANCI-FANCD2) is required for replication-coupled ICL repair; FANCF is an essential upstream core- complex subunit for that pathway. Core biological process (duplicates the IEA ICL-repair annotation). Supporting Evidence: PMID:19965384 The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. |
| GO:0043240 Fanconi anaemia nuclear complex | NAS PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr... | ACCEPT | Summary: Curator statement (ComplexPortal) that FANCF is part of the FA nuclear core complex. Consistent with all other membership evidence. Reason: FANCF is an integral subunit of the FA nuclear core complex characterized in this and related studies. Redundant with the experimental IDA and IBA annotations to the same term but correct. Supporting Evidence: PMID:22343915 Fanconi anemia (FA) nuclear core complex is a multiprotein complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9835411 | KEEP AS NON CORE | Summary: Reactome models a cytosolic FA-core-complex:HSP70 species that binds PKR (PKR-mediated signaling). FANCF is predominantly nuclear, so a cytosolic pool is peripheral and less well established. Reason: Derived from a Reactome PKR-signaling reaction rather than direct FANCF localization data. Retained (author-traceable) but marked non-core because FANCF's characterized localization and function are nuclear; any cytosolic role is minor and not central to FA-pathway ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785126 | ACCEPT | Summary: Reactome ICL-repair reaction (FA core complex assembles at ICLs) placing FANCF in the nucleoplasm. Reason: Consistent with the predominant nuclear/nucleoplasmic localization of FANCF and the FA core complex acting at ICLs in the nucleoplasm. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785342 | ACCEPT | Summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm. Reason: Consistent with the nuclear/nucleoplasmic localization of the FA core complex during ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785361 | ACCEPT | Summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm. Reason: Consistent with the nuclear/nucleoplasmic localization of the FA core complex during ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785732 | ACCEPT | Summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm. Reason: Consistent with the nuclear/nucleoplasmic localization of the FA core complex during ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785986 | ACCEPT | Summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm. Reason: Consistent with the nuclear/nucleoplasmic localization of the FA core complex during ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786155 | ACCEPT | Summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm. Reason: Consistent with the nuclear/nucleoplasmic localization of the FA core complex during ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786166 | ACCEPT | Summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm. Reason: Consistent with the nuclear/nucleoplasmic localization of the FA core complex during ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786171 | ACCEPT | Summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm. Reason: Consistent with the nuclear/nucleoplasmic localization of the FA core complex during ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788385 | ACCEPT | Summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm. Reason: Consistent with the nuclear/nucleoplasmic localization of the FA core complex during ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788392 | ACCEPT | Summary: Reactome ICL-repair reaction placing FANCF in the nucleoplasm. Reason: Consistent with the nuclear/nucleoplasmic localization of the FA core complex during ICL repair. Supporting Evidence: PMID:11063725 FANCF was found predominantly in the nucleus |
| GO:0043240 Fanconi anaemia nuclear complex | IDA PMID:20347428 A histone-fold complex and FANCM form a conserved DNA-remode... | ACCEPT | Summary: Experimental (IDA) demonstration that FANCF is part of the FA core complex, here shown to associate with the FANCM-MHF DNA-remodeling complex that promotes FANCD2 monoubiquitination. Reason: Direct experimental membership evidence; FANCF is an integral subunit of the FA core complex, consistent with all other lines of evidence. Core cellular-component annotation. Supporting Evidence: PMID:20347428 FANCM-MHF associates with the Fanconi anemia (FA) core complex, promotes FANCD2 monoubiquitination in response to DNA damage |
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Download this section (compressed HTML)Q: Does FANCF have any function outside the FA core complex (e.g. the cytosolic FA-core-complex:HSP70:PKR species modeled by Reactome), or is it strictly a nuclear scaffolding subunit?
Q: Are the high-throughput FANCF interactions with TCP11 and HTT biologically meaningful, or are they interactome-screen artifacts?
Experiment: Structure-guided separation-of-function mutations in the FANCF C-terminal adaptor surface (e.g. the loops mutated in PMID:17082180), assayed for core-complex assembly and FANCD2 monoubiquitination.
Hypothesis: Each subcomplex-bridging contact on the FANCF C-terminal adaptor surface contributes independently to core-complex assembly and FANCD2 monoubiquitination.
Experiment: Proximity labeling (BioID/TurboID) of endogenous FANCF in unperturbed vs ICL-damaged cells to define its complete interaction/localization landscape and test for any non-nuclear pool.
Hypothesis: FANCF localization and interactions are restricted to the nucleus/chromatin.
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