FANCE (Fanconi anemia group E protein) is a non-catalytic nuclear subunit of the eight-membered Fanconi anemia (FA) core complex (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM, together with associated FAAP proteins). The FA core complex is a multisubunit RING-type (FANCL-catalyzed) ubiquitin ligase that monoubiquitinates the FANCD2-FANCI (ID2) heterodimer in response to replication-blocking DNA interstrand crosslinks, initiating crosslink repair via nucleolytic incision, translesion synthesis and homologous recombination. Within the complex, FANCE acts as a molecular adaptor that directly binds FANCC and directly binds the downstream substrate FANCD2, thereby bridging the assembled core complex to its substrate; it is also required for the nuclear accumulation of FANCC. FANCE is phosphorylated by the checkpoint kinase CHEK1 (Chk1) at Thr346 and Ser374, a modification dispensable for FANCD2 monoubiquitination but required for full crosslink resistance. Biallelic loss-of-function of FANCE causes Fanconi anemia complementation group E, characterized by bone marrow failure, congenital malformations, cancer predisposition, and cellular hypersensitivity to crosslinking agents with chromosomal instability.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043240 Fanconi anaemia nuclear complex | IBA GO_REF:0000033 | ACCEPT | Summary: FANCE is a bona fide subunit of the Fanconi anemia (FA) core (nuclear) complex. The phylogenetic (IBA) attribution is strongly corroborated by direct experimental evidence, and this is the defining cellular location of FANCE. Reason: FANCE co-purifies with the FANCA/B/C/F/G/L/M core complex and is required for its integrity; membership is experimentally established, making this the correct core cellular-component annotation. Supporting Evidence: PMID:12093742 FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2 PMID:17296736 form a core enzyme complex, required for the monoubiquitination of FANCD2 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: FANCE is a nuclear protein; the UniProt-SubCell mapping to nucleus is correct, although the more specific term nucleoplasm / Fanconi anaemia nuclear complex is also annotated. Reason: Nuclear localization is directly demonstrated experimentally; this broad subcellular-location IEA is accurate. Supporting Evidence: PMID:12093742 FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2 |
| GO:0036297 interstrand cross-link repair | IEA GO_REF:0000002 | ACCEPT | Summary: FANCE participates, as a core-complex subunit, in the FA pathway that repairs DNA interstrand crosslinks. This is a core biological process for FANCE. Reason: The InterPro2GO mapping (FANCE family -> ICL repair) is biologically accurate and matches the experimentally established role of the FA core complex. Supporting Evidence: PMID:19965384 FANCI-FANCD2 is required for replication-coupled ICL repair in S phase PMID:17296736 form a core enzyme complex, required for the monoubiquitination of FANCD2 |
| GO:0043240 Fanconi anaemia nuclear complex | IEA GO_REF:0000002 | ACCEPT | Summary: Duplicate (InterPro-based) assertion of FA nuclear complex membership; correct. Reason: Consistent with the experimentally established core-complex membership of FANCE. Supporting Evidence: PMID:12093742 FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2 |
| GO:0005515 protein binding | IPI PMID:12649160 Fanconi anemia protein complex: mapping protein interactions... | KEEP AS NON CORE | Summary: IPI interaction with FANCC (Q00597) demonstrated by yeast two-hybrid. This is a real, functionally important interaction (a central region of FANCE binds FANCC), but the generic 'protein binding' term is uninformative and does not capture the adaptor function; retained as non-core. Reason: Valid experimental interaction evidence underlying FANCE's adaptor role, but GO:0005515 is too generic to represent a core molecular function. The informative function (protein-macromolecule adaptor activity) is captured in core_functions and as a NEW annotation. Supporting Evidence: PMID:12649160 A central region of FANCE was sufficient for FANCC binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: IPI interaction with FANCC (Q00597) from a proteome-scale AP-MS interactome (BioPlex). Corroborates the FANCE-FANCC interaction but the generic term is uninformative; retained as non-core. Reason: High-throughput interaction data consistent with the known FANCE-FANCC interaction; the uninformative 'protein binding' term is not a core molecular function. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | KEEP AS NON CORE | Summary: IPI interaction with AKT1 (P31749) reported from a systematic screen of mutation-directed neo-protein-protein interactions in cancer. This is a context-specific interaction, not part of FANCE's core crosslink-repair biology. Reason: Reported interaction (also listed in UniProt INTERACTION as Q9HB96-P31749) but of uncertain physiological relevance to FANCE's canonical function; the generic 'protein binding' term is not a core molecular function. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) localizes FANCE to the nucleoplasm, consistent with its role as a nuclear FA core-complex subunit. Reason: Direct localization evidence; nucleoplasm is an accurate and appropriately specific cellular-component annotation. Supporting Evidence: PMID:12093742 FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2 |
| GO:0000785 chromatin | IDA PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr... | ACCEPT | Summary: The FA nuclear core complex (of which FANCE is a subunit) is loaded onto chromatin in response to DNA damage; ComplexPortal annotates the complex, and hence FANCE, to chromatin. Reason: Chromatin association of the FA core complex upon DNA damage is well established; this localization is accurate for FANCE as a complex subunit. Supporting Evidence: PMID:22343915 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: Pathway-level (NAS) attribution of FANCE to interstrand crosslink repair via the FA pathway. Correct core biological process. Reason: The FA pathway, which FANCE enables as a core-complex subunit upstream of FANCD2 monoubiquitination, 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 | NAS PMID:22343915 FAAP20: a novel ubiquitin-binding FA nuclear core-complex pr... | ACCEPT | Summary: NAS assertion of FANCE membership in the FA nuclear core complex; correct. Reason: Consistent with experimental evidence for FANCE core-complex membership. Supporting Evidence: PMID:22343915 FAAP20 is an integral component of the FA nuclear core complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9835411 | KEEP AS NON CORE | Summary: Cytosol localization derived from a Reactome model of a cytoplasmic FA core complex:HSP70 role in PKR-mediated signaling. FANCE is predominantly nuclear; this cytosolic assignment reflects a non-canonical, peripheral role and is not a core location. Reason: FANCE's characterized function is nuclear (FA core complex, FANCD2 activation). The cytosol annotation comes from a specific Reactome PKR-signaling model rather than FANCE's canonical crosslink-repair biology; retained but marked non-core rather than removed, as it derives from a curated pathway model. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785126 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization within the FA core complex assembly at ICLs; consistent with FANCE's nuclear function. Reason: Correct nuclear localization from a curated pathway; consistent with the IDA nucleoplasm annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785342 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization (FANCD2:FANCI/UBE2T binding step); correct nuclear location for FANCE. Reason: Correct nuclear localization from a curated pathway; consistent with other nucleoplasm annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785361 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization (FANCD2:FANCI monoubiquitination step); correct nuclear location. Reason: Correct nuclear localization from a curated pathway; consistent with other nucleoplasm annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785732 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE. Reason: Correct nuclear localization from a curated pathway; consistent with other nucleoplasm annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785986 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE. Reason: Correct nuclear localization from a curated pathway; consistent with other nucleoplasm annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786155 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE. Reason: Correct nuclear localization from a curated pathway; consistent with other nucleoplasm annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786166 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE. Reason: Correct nuclear localization from a curated pathway; consistent with other nucleoplasm annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786171 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization (FANCD2 deubiquitination step); correct nuclear location for FANCE. Reason: Correct nuclear localization from a curated pathway; consistent with other nucleoplasm annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788385 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE. Reason: Correct nuclear localization from a curated pathway; consistent with other nucleoplasm annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788392 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization (ATR phosphorylation step); correct nuclear location for FANCE. Reason: Correct nuclear localization from a curated pathway; consistent with other nucleoplasm annotations. |
| GO:0043240 Fanconi anaemia nuclear complex | IDA PMID:22266823 Regulation of Rev1 by the Fanconi anemia core complex. | ACCEPT | Summary: Direct (IDA) demonstration that FANCE is a component of the FA core complex, co-immunoprecipitating with FANCA and FANCC. Reason: Experimental co-purification establishes FANCE core-complex membership; this is the defining cellular component for FANCE. Supporting Evidence: PMID:22266823 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: FANCE identified as part of the FA core complex, which associates with the FANCM-MHF DNA-remodeling complex. Reason: Consistent, experimentally supported core-complex membership for FANCE. Supporting Evidence: PMID:20347428 FANCM-MHF associates with the Fanconi anemia (FA) core complex |
| GO:0005634 nucleus | NAS PMID:11001585 Isolation of a cDNA representing the Fanconi anemia compleme... | ACCEPT | Summary: The original FANCE cloning paper described a predicted nuclear localization signal and inferred nuclear localization (NAS). Subsequent experimental work confirmed the nuclear location. Reason: Nuclear localization is correct and later directly demonstrated; consistent with the other nucleus/nucleoplasm annotations. |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:12093742 FANCE: the link between Fanconi anaemia complex assembly and... | NEW | Summary: FANCE functions as a molecular adaptor/bridge, directly binding both FANCC (and the FA core complex) and the downstream substrate FANCD2, physically linking the core complex to its substrate. This is FANCE's defining, informative molecular function (in contrast to the generic 'protein binding' annotations). Reason: No informative molecular-function term is present in GOA (only GO:0005515). FANCE binds two partners (FANCC and FANCD2) to coordinate their function, matching the definition of molecular adaptor activity (bringing molecules together to act in a coordinated way). Supported by direct interaction and functional-bridging evidence. Supporting Evidence: PMID:12093742 provides a critical bridge between the FA complex and FANCD2 PMID:12093742 FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2 PMID:12649160 Direct interaction between FANCE and FANCD2 was also demonstrated in the yeast 2-hybrid system PMID:16513431 FANCE is predominantly localized in the nucleus and acts as a molecular bridge between the FA core complex and FANCD2, through direct binding of both FANCC and FANCD2 PMID:16127171 FANCE is shown to be a key mediator of protein interactions both in the architecture of the FA protein complex and in the connection of complex components to the putative downstream targets of complex activity |
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