Fanconi anemia: mechanistic insights into a phenotypically diverse disease using divers model systems

Abstract

Fanconi anemia (FA) is a rare recessive genetic disease characterized by developmental abnormalities, bone marrow failure and cancer predisposition. Cells from FA patients display hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents, which manifests as reduced cell survival, chromosomal aberrations and disturbed cell cycle with a G2-phase arrest. The currently known 15 genes whose mutation has been identified as cause of FA are thought to function in a common pathway involved in the repair of ICLs, the FA pathway. The biochemical function of the 15 FA proteins has remained largely unknown, in part due to the fact that most FA proteins lack distinct functional domains. Deciphering the role of the FA proteins has been a major focus over the last years and has been dominated by studying ICL repair in a variety of model systems. In this review, I will discuss in detail four vertebrate model systems that have provided valuable insights into the function of the FA proteins in ICL repair. These model systems have greatly enhanced the knowledge of the molecular mechanism of ICL repair, the regulation of the FA proteins and the significance of the FA pathway in a whole-organism setting. Although much is still to be learnt, specifically whether and how the defect in ICL repair can be linked to the divers clinical FA phenotype, increasing our knowledge on how the FA pathway acts will further unveil mechanistic clues that will be key in designing therapeutics tailored to each of the defects found in FA patients.