Molecular Genetics of Fanconi Anaemia

Abstract

Cells derived from Fanconi anaemia (FA) patients display hypersensitivity to deoxyribonucleic acid (DNA) cross‐linking agents such as MMC and DEB. Treatment with these agents induces an abnormally prolonged cell cycle arrest in S phase and an accumulation of cells with 4N DNA. Based on this response, the FA pathway has been hypothesised to function in sensing DNA damage induced by these agents and in initiating its repair. This hypothesis has been supported by work elucidating the interactions of FA proteins with proteins known to be involved in DNA‐damage sensing, signalling and repair. Additionally, a significant body of work has pointed to a role of the FA pathway in the cellular response to oxidative stress. Although the exact mechanisms and functions of the FA pathway are yet to be discovered, the interaction of the members of the FA pathway with proteins associated with DNA repair, cellular signalling and oxidative stress management leads to the hypothesis that the FA pathway proteins serve many varied functions throughout the cell. Key Concepts: The FA pathway overlaps significantly with other DNA repair pathways such as homologous recombination, translesion synthesis and mismatch repair. FA pathway proteins are involved in the intricate cellular signalling that occurs following DNA damage. FA pathway proteins are involved in regulating oxidative stress. FA mutant cells display hypersensitivity to DNA damage, particularly DNA crosslink's. FA patients are particularly prone to malignancy, especially myeloid leukemia and squamous cell carcinomas of the head and neck and genitourinary track.