FANCD2

FANCD2 is the central effector of the Fanconi anemia (FA)/BRCA pathway of replication-coupled DNA interstrand crosslink (ICL) repair. Together with its structural paralog FANCI it forms the ID2 heterodimer, which binds DNA with preference for branched structures. When a replication fork stalls at an ICL, FANCD2 is monoubiquitinated on Lys561 by the FA core complex (E3 ligase FANCL with the E2 UBE2T), an event that remodels the open ID2 trough into a closed sliding clamp that encircles duplex DNA and loads the complex onto chromatin. This activated ID2 clamp coordinates the downstream repair reactions: nucleolytic incision (unhooking) of the crosslink, translesion DNA synthesis past the lesion (e.g. via POLN), and homologous recombination, including recruitment of the structure-specific nuclease FAN1 and cooperation with BRCA2/FANCD1. FANCD2 is deubiquitinated by the USP1-UAF1(WDR48) complex once repair is complete. Beyond ICL repair, FANCD2 protects and restarts stalled replication forks, suppresses breakage at common fragile sites, and localizes with BLM to ultrafine anaphase bridges to prevent chromosome missegregation. It is predominantly nuclear, concentrating in damage-induced foci during S phase. Biallelic loss-of-function causes Fanconi anemia complementation group D2, characterized by bone marrow failure, congenital malformations, chromosomal instability, hypersensitivity to crosslinking agents, and cancer predisposition.

Disorders

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