FANCA

FANCA is one of the Fanconi anemia (FA) proteins and an essential structural subunit of the multiprotein FA core complex (also called the Fanconi anaemia nuclear complex), which is composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM together with associated FAAP proteins (FAAP20, FAAP24, FAAP100). The FA core complex is a nuclear multisubunit E3 ubiquitin ligase (with FANCL as the catalytic RING subunit and UBE2T/FANCT as the E2) that, in response to DNA interstrand crosslinks encountered during replication, monoubiquitinates the FANCD2-FANCI (ID2) heterodimer. Monoubiquitinated ID2 is loaded onto chromatin and coordinates downstream nucleolytic incision, translesion synthesis and homologous-recombination repair of the crosslink. FANCA is not the catalytic subunit; it is a large, predominantly alpha-helical scaffolding and protein-interaction hub that binds FANCG and FANCF and directly anchors FAAP20, and it is required for the assembly, stability, nuclear accumulation and chromatin loading of the core complex. The functional form of FANCA is nuclear (a minor pool is cytoplasmic), and its nuclear accumulation depends on FANCC binding and phosphorylation. Biallelic loss-of-function mutations in FANCA are the most common cause of Fanconi anemia (complementation group A, ~60-65% of cases), a chromosomal-instability syndrome with bone-marrow failure, congenital malformations, cellular hypersensitivity to DNA crosslinking agents, and cancer predisposition.

Disorders

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