FANCC

Fanconi anemia group C protein (FANCC) is a non-catalytic subunit of the multiprotein Fanconi anemia (FA) core complex, an E3 ubiquitin ligase that monoubiquitinates the FANCD2-FANCI heterodimer in response to DNA damage. Within the FA core complex FANCC together with FANCE and FANCF forms the substrate-recognition module that positions the FANCD2-FANCI substrate for monoubiquitination by the catalytic FANCL/UBE2T module. FANCC binds directly to FANCE, and its assembly with FANCA is required for integrity and function of the complex; the patient mutation L554P abolishes both interactions and complementing activity. Activated (monoubiquitinated) FANCD2-FANCI then coordinates replication-coupled DNA interstrand cross-link repair, homologous recombination and REV1-dependent translesion synthesis, protecting cells from cross-linking agents and maintaining chromosome stability; loss of FANCC causes Fanconi anemia (bone marrow failure, congenital malformations and cancer predisposition). FANCC exists as a predominantly nuclear form that acts on chromatin and a minor cytoplasmic form; the cytoplasmic pool associates with chaperones (e.g. GRP94/HSP90B1) and has additional, structurally separable roles in cytokine signaling (IFN-gamma/STAT1) and suppression of apoptosis via modulation of the protein kinase PKR (EIF2AK2), together with a proposed role in the cellular response to oxidative stress.

Disorders

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