FANCD2FANCI

FANCD2FANCI refers to the FANCD2–FANCI heterodimer, commonly called the ID complex, a central mediator of the Fanconi anemia (FA) DNA repair pathway. It is formed when the FANCD2 and FANCI proteins associate to function together in recognizing and processing DNA damage, rather than being a gene fusion.

The ID complex plays a pivotal role in coordinating the repair of DNA interstrand crosslinks and other lesions. It binds to damaged DNA at sites of replication stress and serves as a platform to recruit downstream repair factors. Activation occurs when a multisubunit FA core complex monoubiquitinates both FANCD2 and FANCI, leading to a chromatin-associated, ubiquitinated ID complex that coordinates subsequent steps of repair, including incision, translesion synthesis, and homologous recombination through engagement with BRCA1, BRCA2 (FANCD1), PALB2, and RAD51. Deubiquitination by the USP1-UAF1 complex resets the cycle and allows recycling of the components.

Regulation of the ID complex is tightly controlled at the level of ubiquitination and DNA binding. In its unmodified form, the complex participates in sensing DNA damage; upon monoubiquitination, it undergoes conformational changes that enhance interaction with repair factors and stabilize stalled replication forks. Structural studies indicate the complex can adopt clamp-like configurations that encircle DNA, positioning it to coordinate repair at damage sites.

Clinical relevance centers on Fanconi anemia, a genetic disorder characterized by bone marrow failure, congenital abnormalities, and cancer susceptibility resulting from defects in the FA pathway. The FANCD2–FANCI interaction is essential for proper crosslink repair, and disruptions can lead to genomic instability. The ID complex remains a key focus in research on DNA repair, genome stability, and targeted cancer therapies.