Molecular pathogenesis and clinical management of Fanconi anemia

Abstract

Fanconi anemia (FA) is a rare genetic disorder associated with a high frequency of hematological abnormalities and congenital anomalies. Based on multilateral efforts from basic scientists and clinicians, significant advances in our knowledge of FA have been made in recent years. Here we review the clinical features, the diagnostic criteria, and the current and future therapies of FA and describe the current understanding of the molecular basis of the disease.

Figure 1. Pathophysiology of FA.

FA cells are highly vulnerable to endogenous insults, such as ROS, other sources of DNA crosslinkers (e.g., formaldehyde), and exogenous DNA-damaging agents. Repeated exposure to these insults in FA cells during developmental stages can lead to high incidence of congenital abnormalities, bone marrow failure, and cancers.

Figure 2. FA pathway.

ATR-mediated signal activates the FA pathway at the stalled replication forks, leading to the activation of the FA core complex and monoubiquitination of the FANCD2/FANCI heterodimer. ATR phosphorylates multiple FA proteins for activation. Monoubiquitinated D2/I recruits FAN1 nuclease and FANCP (which associates with several nucleases), which might participate in nucleolytic incision near crosslinked DNA. D2/I might recruit TLS polymerases (not shown) and HR factors, including FANCD1 (BRCA2) and RAD51. FANCO (RAD51C) is known to participate in the HR step. The USP1/UAF1 complex deubiquitinates D2/I to complete the pathway. 15 FA proteins (blue) are shown. Other important factors that crosstalk with the FA pathway, such as PCNA, γ-H2AX, TOPBP1, MSH2, TLS polymerases, and BLM complexes, are not shown for simplicity. A DNA ICL (red) is illustrated between the DNA double strand.