Fanconi anemia (FA) pathway complexes (FA pathway)

The Fanconi anemia (FA) pathway complexes represent a sophisticated DNA damage response network essential for the repair of DNA interstrand cross-links (ICLs) (Ceccaldi et al., 2016, Nature Reviews Cancer). The pathway is organized into functional modules: the FA core complex (an E3 ubiquitin ligase), the ID complex (FANCI-FANCD2), and downstream effector proteins including nucleases and homologous recombination factors like BRCA2 (Walden & Deans, 2014, Annual Review of Genetics). Upon sensing replication stress or ICLs, the core complex monoubiquitinates the ID complex, which then localizes to the site of damage to coordinate DNA incision, translesion synthesis, and double-strand break repair (Kottemann & Huang, 2013, Genetics in Medicine). Mutations in any of the 22+ FANC genes result in Fanconi anemia, a syndrome characterized by chromosomal instability, bone marrow failure, and a high risk of squamous cell carcinomas and leukemias (Nalepa & Clapp, 2018, F1000Research). In clinical oncology, the FA pathway is a major target for synthetic lethality; for instance, tumors with FA pathway deficiencies are hypersensitive to PARP inhibitors and DNA-cross-linking agents like cisplatin (Lord & Ashworth, 2016, Nature).

Other names

Fanconi anemia core complexFA/BRCA pathwayFANC complexDNA interstrand cross-link repair pathway

Synthetic lethality via PARP inhibition in FA-deficient cells; induction of DNA interstrand cross-links to exploit repair deficiencies (Lord & Ashworth, 2016, Nature).