A new frontier in Fanconi anemia: From DNA repair to ribosome biogenesis

Abstract

Described by Guido Fanconi almost 100 years ago, Fanconi anemia (FA) is a rare genetic disease characterized by developmental abnormalities, bone marrow failure (BMF) and cancer predisposition. The proteins encoded by FA-mutated genes (FANC proteins) and assembled in the so-called FANC/BRCA pathway have key functions in DNA repair and replication safeguarding, which loss leads to chromosome structural aberrancies. Therefore, since the 1980s, FA has been considered a genomic instability and chromosome fragility syndrome. However, recent findings have demonstrated new and unexpected roles of FANC proteins in nucleolar homeostasis and ribosome biogenesis, the alteration of which impacts cellular proteostasis. Here, we review the different cellular, biochemical and molecular anomalies associated with the loss of function of FANC proteins and discuss how these anomalies contribute to BMF by comparing FA to other major inherited BMF syndromes. Our aim is to determine the extent to which alterations in the DNA damage response in FA contribute to BMF compared to the consequences of the loss of function of the FANC/BRCA pathway on the other roles of the pathway.