FANCE (Fanconi anemia group E protein) — review notes

UniProt: Q9HB96 (FANCE_HUMAN), 536 aa, chromosome 6. HGNC:3586. Gene ID 2178.

Summary of biology

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 FANCD2–FANCI
(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.

Key provenance

Core function: bridge between FA core complex and FANCD2; FANCC nuclear accumulation

PMID:12093742
- PMID:12093742
- PMID:12093742
- PMID:12093742

Direct FANCE–FANCC and FANCE–FANCD2 interactions (yeast 2/3-hybrid)

PMID:12649160
- PMID:12649160
- PMID:12649160
- UniProt FT REGION 150..371 "Interaction with FANCC" (ECO:0000269|PubMed:12649160).

FA core complex membership required for FANCD2 monoubiquitination

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 → phosphorylation has a function independent of FANCD2-Ub. PMID:17296736
- UniProt: MOD_RES 346 Phosphothreonine by CHEK1; MOD_RES 374 Phosphoserine by CHEK1.

Nuclear / chromatin localization

• UniProt SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12093742, ECO:0000269|PubMed:17296736}.
• HPA IDA → nucleoplasm (GO:0005654) GO_REF:0000052.
• ComplexPortal IDA → chromatin (GO:0000785) PMID:22343915 (FA nuclear core complex is chromatin-associated / DNA-damage-induced chromatin loading).

FA nuclear core complex (identification of FANCE as a subunit)

• PMID:22266823 (FANCE identified as part of the FA core complex in this study; UniProt RN[16] "IDENTIFICATION IN THE FA COMPLEX", PMID:22266823).
• PMID:20347428 — FANCM/MHF histone-fold complex study; FANCE is a subunit of the associated FA core complex (UniProt RN[9-11] identify FANCE in complexes with FANCA/B/C/F/G/L/M).
• ComplexPortal CPX-6263 "Fanconi anemia ubiquitin ligase complex".

ICL repair (pathway-level)

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 (IPI) annotations

• PMID:12649160 IPI WITH FANCC (Q00597): direct FANCE–FANCC interaction — real, meaningful (underlies adaptor function).
• PMID:33961781 IPI WITH FANCC (Q00597): BioPlex proteome-scale AP-MS network (high-throughput); corroborates FANCE–FANCC.
• PMID:35512704 IPI WITH AKT1 (P31749): "Systematic discovery of mutation-directed neo-protein-protein interactions in cancer" — high-throughput neo-PPI screen; UniProt INTERACTION lists Q9HB96–P31749 (AKT1), NbExp=4. This is a reported interaction but not part of FANCE's core ICL-repair biology.

Structure

• PDB 2ILR (2.0 Å, residues 273-536): C-terminal helical repeat domain (FANCE_c-term, CDD cd07439; Pfam PF11510 FA_FANCE). The C-terminal domain mediates FANCD2 binding.
• PDB 7KZP–7KZV (cryo-EM): FANCE within the assembled FA core complex.

Disease

• Biallelic FANCE loss-of-function causes Fanconi anemia complementation group E (FANCE; MIM:600901): bone marrow failure, congenital malformations, cancer predisposition; cellular ICL hypersensitivity and chromosome instability. PMID:11001585 (cDNA isolation / complementation group E), variant Q184 PMID:17924555.

Curation decisions (rationale)

• Core MF = molecular adaptor activity (GO:0060090): FANCE bridges FANCC/FA core complex to FANCD2. No specific catalytic MF (FANCE is non-catalytic; FANCL is the ligase).
• Core CC = Fanconi anaemia nuclear complex (GO:0043240).
• Core BP = interstrand cross-link repair (GO:0036297).
• protein binding (GO:0005515) annotations: kept as non-core (uninformative term, but valid interaction evidence). The AKT1 neo-PPI is non-core cancer-context.
• Reactome nucleoplasm TAS annotations (11 of them) all point to the same location; accept/keep-as-non-core (localization, correct but redundant).