Fanconi anemia and the cell cycle: new perspectives on aneuploidy

Abstract

Fanconi anemia (FA) is a complex heterogenic disorder of genomic instability, bone marrow failure, cancer predisposition, and congenital malformations. The FA signaling network orchestrates the DNA damage recognition and repair in interphase as well as proper execution of mitosis. Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis. Thus, the FA genes function as guardians of genome stability throughout the cell cycle. This review discusses recent advances in diagnosis and clinical management of Fanconi anemia and presents the new insights into the origins of genomic instability in FA. These new discoveries may facilitate the development of rational therapeutic strategies for FA and for FA-deficient malignancies in the general population.

Figure 1.. Fanconi anemia (FA) signaling is essential for DNA damage repair in interphase

DNA damage in interphase due to genotoxic stress stimulates the DNA damage kinase network, which triggers assembly of the FA core complex followed by monoubiquitination of the FANCD2/FANCI heterodimer and activation of DNA damage repair processes. Abbreviations: Ub, ubiquitination.

Figure 2.. Fanconi anemia (FA) signaling pathway guards the genome throughout the cell cycle

FA signaling prevents accumulation of DNA damages in interphase and ensures high-fidelity chromosome segregation in mitosis. Abbreviations: SAC, spindle assembly checkpoint.