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
|
FANCE is a nuclear subunit of the Fanconi anemia (FA) core complex that functions as a molecular bridge coupling the core complex to its downstream substrate, the FANCD2-FANCI heterodimer [PMID:12093742, PMID:16127171]. It binds FANCC directly and, through a distinct region, contacts FANCD2, thereby recruiting the substrate for monoubiquitination; FANCE is required for nuclear accumulation of FANCC, formation of the FANCA-FANCC complex, FANCD2 monoubiquitination, and FANCD2 nuclear foci assembly [PMID:12093742, PMID:12239156, PMID:16513431]. The FANCC-binding and FANCD2-binding surfaces are separable, and the extreme C-terminal residue phenylalanine 522 is the critical determinant of the FANCD2/FANCI interaction required for substrate monoubiquitination and DNA cross-link repair [PMID:16513431, PMID:24451376]. Structurally FANCE adopts a repeated helical (HEAT-like) fold, and disease-associated mutations map to this domain and disrupt the FANCE-FANCD2 interaction PMID:17308347. Beyond its scaffolding role, FANCE is directly phosphorylated by Chk1 at threonine 346 and serine 374 upon DNA damage, an event dispensable for FANCD2 monoubiquitination but required for cross-link repair, defining a separable monoubiquitination-independent function PMID:17296736. The FANCC-FANCE-FANCF subcomplex is evolutionarily conserved and additionally acts to suppress meiotic crossovers PMID:36652992.
| Year | Confidence | Finding | PMIDs | Journal |
|---|---|---|---|---|
| 2002 | High | FANCE is a component of the nuclear FA core complex, binding directly to both FANCC and FANCD2. FANCE is required for nuclear accumulation of FANCC, formation of the FANCA-FANCC complex, monoubiquitination of FANCD2, and FANCD2 nuclear foci assembly. Disease-associated FANCC mutants that do not bind FANCE cannot accumulate in the nucleus and are unable to prevent chromosome breakage. | PMID:12093742 | The EMBO journal |
| 2002 | High | FANCE promotes nuclear accumulation of FANCC and is itself a nuclear protein that co-immunoprecipitates with FANCA, FANCC, and FANCG (but not FANCD2) in normal cells. FANCE is required for monoubiquitination of FANCD2 and downstream events in the FA pathway. | PMID:12239156 | Blood |
| 2005 | High | FANCE mediates a ternary complex with FANCC and FANCD2. Using yeast three-hybrid and two-hybrid systems confirmed in human cells, FANCE bridges FANCC and FANCD2. FANCE mutants that interact with FANCC but not FANCD2 abolish FANCD2 monoubiquitination and sensitize cells to DNA cross-linkers. FANCE also mediates interaction between FANCC and FANCF within the core complex. | PMID:16127171 | The Journal of biological chemistry |
| 2007 | High | In response to DNA damage, Chk1 directly phosphorylates FANCE at two conserved sites: threonine 346 and serine 374. Phosphorylated FANCE assembles into nuclear foci and co-localizes with FANCD2. A non-phosphorylatable FANCE mutant (T346A/S374A) permits FANCD2 monoubiquitination and foci formation but fails to complement MMC hypersensitivity, indicating a FANCD2 monoubiquitination-independent function of Chk1-mediated FANCE phosphorylation in DNA cross-link repair. | PMID:17296736 | Molecular and cellular biology |
| 2007 | High | Crystal structure of human FANCE reveals a repeated helical motif (HEAT-like repeats). The crystallographically defined portion of FANCE is sufficient for interaction with FANCD2. Disease-associated mutations in FANCE disrupt the FANCE-FANCD2 interaction, providing structural insight into FA pathogenesis. | PMID:17308347 | Nucleic acids research |
| 2006 | Medium | Nuclear accumulation of FANCE depends on FANCC but not on other FA proteins (FANCA, FANCG, FANCF). Adding a nuclear export signal does not prevent FANCE nuclear localization, indicating the NLS motifs alone are not sufficient. The region of FANCE that binds FANCC is distinct from the region that binds FANCD2, supporting a model in which FANCE recruits FANCD2 to the core complex independently of FANCC binding. | PMID:16513431 | DNA repair |
| 2014 | High | The extreme C-terminus of FANCE (phenylalanine 522) is a critical residue for mediating monoubiquitination of the FANCD2-FANCI complex. An interaction-deficient FANCE mutant (disrupting FANCE-FANCD2 binding at the C-terminus) confers cellular sensitivity to cisplatin comparable to FANCE-null cells. Ectopic expression of the FANCE C-terminus fragment alone in normal cells disrupts DNA repair, confirming the FANCE-FANCD2 interaction is required for DNA cross-link repair. | PMID:24451376 | The Journal of biological chemistry |
| 1999 | Medium | The FANCE gene was mapped to chromosome 6p21-22 using homozygosity mapping and genetic linkage analysis in FA complementation group E families. | PMID:10205272 | American journal of human genetics |
| 2015 | Medium | A splice isoform of FANCE (FANCEΞ4, lacking exon 4) is expressed in normal and breast cancer cell lines. FANCEΞ4 is translated into a nuclear protein but cannot support FANCD2 or FANCI monoubiquitination, fails to rescue MMC-induced G2/M block or cell survival in FANCE-deficient cells, and promotes degradation of FANCD2 protein. FANCEΞ4 interacts with wild-type FANCE and may act as a dominant negative regulator of FANCE activity. | PMID:26277624 | Journal of molecular biology |
| 2023 | Medium | The FANCC-FANCE-FANCF subcomplex is evolutionarily conserved from vertebrates to plants (Arabidopsis). In Arabidopsis meiosis, FANCC, FANCE, and FANCF form a physical complex and act together as anti-crossover factors. Loss of any one of the three genes partially rescues CO-defective mutants and causes synthetic meiotic catastrophe with the pro-CO factor MUS81. | PMID:36652992 | Nucleic acids research |
UniProt: Q9HB96 (FANCE_HUMAN), 536 aa, chromosome 6. HGNC:3586. Gene ID 2178.
FANCE is one of the eight subunits of the Fanconi anemia (FA) core complex
(FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, plus associated FAAP
proteins). The FA core complex is a nuclear multisubunit E3 ubiquitin ligase
(the catalytic RING subunit is FANCL) that monoubiquitinates the FANCD2βFANCI
(ID2) heterodimer in response to replication-blocking DNA interstrand crosslinks
(ICLs), triggering downstream ICL repair by nucleolytic incision, translesion
synthesis and homologous recombination.
FANCE's specific, distinguishing role within the core complex is that of a
molecular bridge/adaptor: it directly binds FANCC and directly binds the
substrate FANCD2, thereby physically linking the assembled core complex to its
downstream substrate. FANCE is also required for the nuclear accumulation of
FANCC.
PMID:12093742
- PMID:12093742
- PMID:12093742
- PMID:12093742
PMID:12649160
- PMID:12649160
- PMID:12649160
- UniProt FT REGION 150..371 "Interaction with FANCC" (ECO:0000269|PubMed:12649160).
PMID:17296736
- PMID:17296736
- PMID:17296736
- Chk1 directly phosphorylates FANCE at Thr346 and Ser374; the non-phosphorylatable FANCE(T346A/S374A) still supports FANCD2 monoubiquitination and foci but fails to complement MMC hypersensitivity β phosphorylation has a function independent of FANCD2-Ub. PMID:17296736
- UniProt: MOD_RES 346 Phosphothreonine by CHEK1; MOD_RES 374 Phosphoserine by CHEK1.
PMID:19965384
- PMID:19965384
- Note: this NAS annotation on FANCE is a pathway-level attribution (the paper itself studies FANCI-FANCD2 in Xenopus egg extracts; FANCE participates as a core-complex subprovider upstream of FANCD2 monoubiquitination).
protein binding (GO:0005515) annotations: kept as non-core (uninformative term, but valid interaction evidence). The AKT1 neo-PPI is non-core cancer-context.id: Q9HB96
gene_symbol: FANCE
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
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.
existing_annotations:
- term:
id: GO:0043240
label: Fanconi anaemia nuclear complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:12093742
supporting_text: FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2
- reference_id: PMID:17296736
supporting_text: form a core enzyme complex, required for the monoubiquitination of FANCD2
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
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.
action: ACCEPT
reason: >-
Nuclear localization is directly demonstrated experimentally; this broad
subcellular-location IEA is accurate.
supported_by:
- reference_id: PMID:12093742
supporting_text: FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2
- term:
id: GO:0036297
label: interstrand cross-link repair
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
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.
action: ACCEPT
reason: >-
The InterPro2GO mapping (FANCE family -> ICL repair) is biologically accurate and
matches the experimentally established role of the FA core complex.
supported_by:
- reference_id: PMID:19965384
supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase
- reference_id: PMID:17296736
supporting_text: form a core enzyme complex, required for the monoubiquitination of FANCD2
- term:
id: GO:0043240
label: Fanconi anaemia nuclear complex
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: part_of
review:
summary: >-
Duplicate (InterPro-based) assertion of FA nuclear complex membership; correct.
action: ACCEPT
reason: >-
Consistent with the experimentally established core-complex membership of FANCE.
supported_by:
- reference_id: PMID:12093742
supporting_text: FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12649160
qualifier: enables
review:
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.
action: KEEP_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.
supported_by:
- reference_id: PMID:12649160
supporting_text: A central region of FANCE was sufficient for FANCC binding
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
qualifier: enables
review:
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.
action: KEEP_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.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:35512704
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: >-
Immunofluorescence (HPA) localizes FANCE to the nucleoplasm, consistent with its
role as a nuclear FA core-complex subunit.
action: ACCEPT
reason: >-
Direct localization evidence; nucleoplasm is an accurate and appropriately specific
cellular-component annotation.
supported_by:
- reference_id: PMID:12093742
supporting_text: FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2
- term:
id: GO:0000785
label: chromatin
evidence_type: IDA
original_reference_id: PMID:22343915
qualifier: located_in
review:
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.
action: ACCEPT
reason: >-
Chromatin association of the FA core complex upon DNA damage is well established;
this localization is accurate for FANCE as a complex subunit.
supported_by:
- reference_id: PMID:22343915
supporting_text: 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: >-
Pathway-level (NAS) attribution of FANCE to interstrand crosslink repair via the FA
pathway. Correct core biological process.
action: ACCEPT
reason: >-
The FA pathway, which FANCE enables as a core-complex subunit upstream of FANCD2
monoubiquitination, is required for replication-coupled ICL repair.
supported_by:
- reference_id: PMID:19965384
supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase
- term:
id: GO:0043240
label: Fanconi anaemia nuclear complex
evidence_type: NAS
original_reference_id: PMID:22343915
qualifier: part_of
review:
summary: >-
NAS assertion of FANCE membership in the FA nuclear core complex; correct.
action: ACCEPT
reason: >-
Consistent with experimental evidence for FANCE core-complex membership.
supported_by:
- reference_id: PMID:22343915
supporting_text: 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: >-
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6785126
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization within the FA core complex assembly at ICLs;
consistent with FANCE's nuclear function.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with the IDA
nucleoplasm annotation.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6785342
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization (FANCD2:FANCI/UBE2T binding step); correct
nuclear location for FANCE.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with other
nucleoplasm annotations.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6785361
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization (FANCD2:FANCI monoubiquitination step);
correct nuclear location.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with other
nucleoplasm annotations.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6785732
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with other
nucleoplasm annotations.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6785986
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with other
nucleoplasm annotations.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786155
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with other
nucleoplasm annotations.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786166
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with other
nucleoplasm annotations.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786171
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization (FANCD2 deubiquitination step); correct
nuclear location for FANCE.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with other
nucleoplasm annotations.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6788385
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization; correct nuclear location for FANCE.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with other
nucleoplasm annotations.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6788392
qualifier: located_in
review:
summary: >-
Reactome (TAS) nucleoplasm localization (ATR phosphorylation step); correct nuclear
location for FANCE.
action: ACCEPT
reason: >-
Correct nuclear localization from a curated pathway; consistent with other
nucleoplasm annotations.
- term:
id: GO:0043240
label: Fanconi anaemia nuclear complex
evidence_type: IDA
original_reference_id: PMID:22266823
qualifier: part_of
review:
summary: >-
Direct (IDA) demonstration that FANCE is a component of the FA core complex,
co-immunoprecipitating with FANCA and FANCC.
action: ACCEPT
reason: >-
Experimental co-purification establishes FANCE core-complex membership; this is the
defining cellular component for FANCE.
supported_by:
- reference_id: PMID:22266823
supporting_text: 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: >-
FANCE identified as part of the FA core complex, which associates with the
FANCM-MHF DNA-remodeling complex.
action: ACCEPT
reason: >-
Consistent, experimentally supported core-complex membership for FANCE.
supported_by:
- reference_id: PMID:20347428
supporting_text: FANCM-MHF associates with the Fanconi anemia (FA) core complex
- term:
id: GO:0005634
label: nucleus
evidence_type: NAS
original_reference_id: PMID:11001585
qualifier: located_in
review:
summary: >-
The original FANCE cloning paper described a predicted nuclear localization signal
and inferred nuclear localization (NAS). Subsequent experimental work confirmed the
nuclear location.
action: ACCEPT
reason: >-
Nuclear localization is correct and later directly demonstrated; consistent with
the other nucleus/nucleoplasm annotations.
- term:
id: GO:0030674
label: protein-macromolecule adaptor activity
evidence_type: IDA
original_reference_id: PMID:12093742
qualifier: enables
review:
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).
action: NEW
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.
supported_by:
- reference_id: PMID:12093742
supporting_text: provides a critical bridge between the FA complex and FANCD2
- reference_id: PMID:12093742
supporting_text: FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2
- reference_id: PMID:12649160
supporting_text: Direct interaction between FANCE and FANCD2 was also demonstrated in the yeast 2-hybrid system
- reference_id: PMID:16513431
supporting_text: 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
- reference_id: PMID:16127171
supporting_text: 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
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:11001585
title: Isolation of a cDNA representing the Fanconi anemia complementation group
E gene.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Original identification/cloning of the FANCE gene (complementation group E);
establishes disease association and predicted nuclear localization. Abstract-only
in cache.
- id: PMID:12093742
title: 'FANCE: the link between Fanconi anaemia complex assembly and activity.'
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Full text verified. Definitive functional paper: FANCE binds FANCC and FANCD2,
bridges the FA core complex to FANCD2, and is required for FANCC nuclear
accumulation. Anchors the protein-macromolecule adaptor activity and FA-complex annotations.
- 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: >-
Maps direct FANCE-FANCC (central region of FANCE) and FANCE-FANCD2 interactions by
yeast two-hybrid; source of the FANCE IPI(FANCC) annotation and supports adaptor
function. Abstract-only but interactions are clearly stated.
- 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: >-
Establishes that the FA pathway (FANCI-FANCD2 monoubiquitination) drives
replication-coupled ICL repair; pathway-level support for the FANCE ICL-repair BP
annotation. Studies FANCD2/FANCI directly rather than FANCE.
- id: PMID:20347428
title: A histone-fold complex and FANCM form a conserved DNA-remodeling complex
to maintain genome stability.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Characterizes the FANCM-MHF complex that associates with the FA core complex;
FANCE is a subunit of that associated core complex.
- id: PMID:22266823
title: Regulation of Rev1 by the Fanconi anemia core complex.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Full text verified. Co-purification places FANCE with FANCA and FANCC in the FA
core complex; source of the FANCE IDA FA-complex annotation. Primary focus is
FAAP20/Rev1 but FANCE membership is explicitly shown.
- 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: >-
Characterizes FAAP20 as an integral FA nuclear core-complex component and
DNA-damage-induced chromatin loading of the complex; supports the chromatin and
FA-complex annotations (ComplexPortal-assigned to FANCE as a complex member).
- 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: >-
Proteome-scale BioPlex AP-MS interactome; source of a high-throughput FANCE-FANCC
IPI. Corroborative but low-specificity.
- id: PMID:35512704
title: Systematic discovery of mutation-directed neo-protein-protein interactions
in cancer.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: >-
Systematic neo-PPI screen in cancer; source of the FANCE-AKT1 IPI. Interaction is
context-specific and not part of FANCE's canonical crosslink-repair function.
- id: PMID:17296736
title: Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA
pathway.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Full text verified. Confirms FANCE as a core-complex subunit that promotes FANCD2
monoubiquitination; shows Chk1 phosphorylates FANCE at Thr346/Ser374, required for
crosslink resistance independent of FANCD2-Ub.
- id: PMID:12239156
title: The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of FANCC.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Abstract verified. Shows FANCE is a component of the nuclear FA core complex in vivo
(co-IPs with FANCA/FANCC/FANCG but not FANCD2) and that FANCE restores nuclear
accumulation of FANCC, FANCA-FANCC complex formation, and FANCD2 monoubiquitination
in FA-E cells. Supports the FANCC nuclear-accumulation and FA-complex-membership
claims.
- id: PMID:16127171
title: FANCC, FANCE, and FANCD2 form a ternary complex essential to the integrity of
the Fanconi anemia DNA damage response pathway.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Abstract verified. Demonstrates FANCE mediates the FANCC-FANCD2 interaction
(ternary complex) in yeast three-hybrid and human cells, and that FANCE mutants that
bind FANCC but not FANCD2 abolish FANCD2 monoubiquitination and confer cross-linker
sensitivity. Also shows FANCE mediates FANCC-FANCF association. Directly supports the
protein-macromolecule adaptor activity annotation.
- id: PMID:16513431
title: The nuclear accumulation of the Fanconi anemia protein FANCE depends on FANCC.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Abstract verified. States explicitly that FANCE acts as a molecular bridge between
the FA core complex and FANCD2 through direct binding of both FANCC and FANCD2, and
that the FANCC-binding region is distinct from the FANCD2-binding region. Strong
support for the protein-macromolecule adaptor activity annotation.
- id: PMID:24451376
title: The carboxyl terminus of FANCE recruits FANCD2 to the Fanconi Anemia (FA) E3
ligase complex to promote the FA DNA repair pathway.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Full text verified. Maps the FANCD2-interacting region to the extreme C-terminus of
FANCE and identifies Phe-522 as a critical residue for recruiting FANCD2 and
inducing FANCD2-FANCI monoubiquitination; an interaction-deficient mutant confers
cisplatin/MMC sensitivity comparable to FANCE-null while preserving core-complex
integrity. Corroborates the substrate-adaptor / bridging function.
- 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-9835411
title: FA core complex:HSP70s binds PKR
findings: []
core_functions:
- description: >-
Molecular adaptor within the Fanconi anemia core complex: FANCE directly binds FANCC
(bridging into the assembled FA core complex) and directly binds the substrate FANCD2,
physically linking the core complex to its downstream substrate and thereby promoting
DNA-damage-induced FANCD2 monoubiquitination and interstrand crosslink repair. FANCE
is also required for the nuclear accumulation of FANCC.
supported_by:
- reference_id: PMID:12093742
supporting_text: provides a critical bridge between the FA complex and FANCD2
- reference_id: PMID:12093742
supporting_text: FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2
- reference_id: PMID:12649160
supporting_text: A central region of FANCE was sufficient for FANCC binding
- reference_id: PMID:24451376
supporting_text: the Phe-522 within the region is a critical residue for the ability of FANCE to recruit FANCD2 to the FA core complex and to induce the subsequent monoubiquitination reaction
- reference_id: PMID:12239156
supporting_text: FANCE is a component of the nuclear FA complex in vivo and is required for the monoubiquitination of FANCD2
molecular_function:
id: GO:0030674
label: protein-macromolecule adaptor activity
directly_involved_in:
- id: GO:0036297
label: interstrand cross-link repair
locations:
- id: GO:0005654
label: nucleoplasm
in_complex:
id: GO:0043240
label: Fanconi anaemia nuclear complex