FANCA (human) — gene review notes

UniProt: O15360 (FANCA_HUMAN), 1455 aa. Gene on 16q24.3. Synonyms FAA, FACA, FANCH.
Accounts for ~60-65% of Fanconi anemia cases.

Summary of function

FANCA is one of the eight Fanconi anemia (FA) proteins (FANCA, B, C, E, F, G,
L/PHF9, M) that assemble into the multisubunit FA core complex (FA nuclear
complex; GO:0043240; ComplexPortal CPX-6263 "Fanconi anemia ubiquitin ligase
complex"). The core complex is a nuclear E3 ubiquitin-ligase assembly (catalytic
RING subunit = FANCL, E2 = UBE2T/FANCT) that, in response to DNA interstrand
crosslinks (ICLs) encountered during replication, monoubiquitinates the
FANCD2-FANCI (ID2) heterodimer. Monoubiquitinated ID2 is loaded onto chromatin
and coordinates downstream nucleolytic incision, translesion synthesis (TLS), and
homologous-recombination repair. FANCA itself is not the catalytic subunit; it is
a large scaffolding/docking subunit and the principal protein-protein interaction
hub of the core complex.

Key provenance

Positional cloning / identity

• PMID:8896564

Nuclear complex membership (GO:0043240)

• PMID:9398857 and
  PMID:9398857
• PMID:11063725
• PMID:12649160
• PMID:22343915
• PMID:22266823
• UniProt SUBUNIT: "Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM."

Interstrand cross-link repair (GO:0036297) / DNA repair (GO:0006281)

• PMID:19965384 — FANCA is a core-complex subunit required for this activation.
• PMID:22266823 and
  PMID:22266823

Subcellular location

• Nucleus (major functional form) and cytoplasm (minor form):
  UniProt SUBCELLULAR LOCATION "Nucleus. Cytoplasm. Note=The major form is nuclear. The minor form is cytoplasmic."
• PMID:9398857
• Nuclear localization + phosphorylation required for function (UniProt refs PMID:9742112, PMID:9789045; NLS motif 18-34).
• Chromatin loading is DNA-damage-induced: PMID:22343915

Protein interactions (all GO:0005515 protein binding — uninformative MF; scaffold/hub role)

FANCA is the central interaction hub of the core complex. Verified partners in cached lit:
- FANCG (O15287): PMID:10627486;
PMID:10652215;
PMID:12649160
- FANCF (Q9NPI8): PMID:11063725
- FAAP24 (via FANCM), FAAP100 (Q0VG06): PMID:17396147; PMID:17289582 FAAP24 targets FANCM.
- FAAP20/C1orf86 (Q6NZ36): PMID:22343915, PMID:22705371, PMID:22266823
- SMARCA4/BRG1 (P51532), SWI/SNF: PMID:11726552; PMID:11726552
- ERCC4/XPF (Q92889) + nonerythroid αII-spectrin: PMID:12571280
- GRB2 (P62993): SH3 peptide-array screen PMID:17474147 — high-throughput, peripheral.
- Large-scale interactome / proteomics screens (FANCG or FAAP100 baits): PMID:16189514, PMID:28514442, PMID:32814053, PMID:33961781, PMID:35271311, PMID:37398436, PMID:40205054 — high-throughput, uninformative.

regulation of regulatory T cell differentiation (GO:0045589, IBA)

Phylogenetic (PANTHER/GO_Central) inference seeded from mouse Fanca (MGI:1341823).
Peripheral/pleiotropic; not a core molecular function of the DNA-repair scaffold.
Treat as non-core.

protein-containing complex assembly (GO:0065003, TAS PMID:9398857)

FANCA is required for formation/stability of the FA core complex (binds FANCG/FANCF/FAAP20;
regulates FAAP20 stability). Genuine but essentially a restatement of complex membership.

Structure

Cryo-EM structures of the human FA core complex: PDB 7KZP/7KZQ/7KZR/7KZS/7KZT/7KZV
(1-1455). FANCA is largely α-helical (Pfam FANCA_arcN, FANCA_helical, FANCA_CTD, Fanconi_A_N).

Action plan for annotations

• GO:0043240 FA nuclear complex (IBA/IEA/NAS/IDA x7): ACCEPT (core; must be consistent).
• GO:0005515 protein binding (all IPI): MARK_AS_OVER_ANNOTATED (uninformative; hub role captured in core_functions/notes).
• GO:0036297 ICL repair (IEA/NAS): ACCEPT (core BP).
• GO:0006281 DNA repair (TAS): ACCEPT (correct broader BP).
• GO:0005634 nucleus (IEA/IDA/TAS): ACCEPT (functional location).
• GO:0005654 nucleoplasm (IDA/TAS x10): ACCEPT.
• GO:0000785 chromatin (IDA): ACCEPT (DNA-damage-induced loading).
• GO:0005737 cytoplasm (IEA/TAS): KEEP_AS_NON_CORE (minor/inactive form).
• GO:0005829 cytosol (TAS): KEEP_AS_NON_CORE.
• GO:0065003 complex assembly (TAS): ACCEPT.
• GO:0045589 Treg differentiation (IBA): KEEP_AS_NON_CORE (pleiotropic, mouse-ortholog-derived).