Recent insights into the molecular basis of Fanconi anemia: genes, modifiers, and drivers

Abstract

Fanconi anemia (FA), the most common form of inherited bone marrow failure, predisposes to leukemia and solid tumors. FA is caused by the genetic disruption of a cellular pathway that repairs DNA interstrand crosslinks. The impaired function of this pathway, and the genetic instability that results, is considered the main pathogenic mechanism behind this disease. The identification of breast cancer susceptibility genes (for example, BRCA1/FANCS and BRCA2/FANCD1) as being major players in the FA pathway has led to a surge in molecular studies, resulting in the concept of the FA-BRCA pathway. In this review, we discuss recent advances in the molecular pathogenesis of FA from three viewpoints: (a) new FA genes, (b) modifier pathways that influence the cellular and clinical phenotypes of FA and (c) non-canonical functions of FA genes that may drive disease progression independently of deficient DNA repair. Potential therapeutic approaches for FA that are relevant to each will also be proposed.

Keywords: Aldehydes; Autophagy; Bone marrow failure; DNA interstrand crosslink repair; TGFβ.

Fig. 1

A framework of how studies on the molecular pathogenesis of FA can improve understanding of disease progression. Identifying new FA genes leads to a more complete knowledge of those proteins involved in the canonical FA pathway. Modifier pathways contribute to FA by increasing the demands of DNA repair in cells that are deficient in the FA pathway. Drivers are DNA repair-independent (non-canonical) functions of FA genes that may contribute to disease progression. Potential therapeutic approaches that arise from the studies discussed in this review are bulleted

Fig. 2

Schematic of the canonical FA pathway. FA genes can be organized by their relationship to FANCI/D2 monoubiquitination. The most recently identified FA genes (discussed in this review) are bolded in red. Because FANCV/REV7 has multiple activities, whether its polymerase function is the most relevant to FA is unclear

Fig. 3

Modifier pathways that influence FA disease progression that are discussed in this review. Aldehydes act as a source of endogenous ICLs. In the context of an impaired FA pathway, overcoming the ability of aldehyde detoxifying enzymes to metabolize aldehydes results in the accumulation of ICLs that exacerbate disease progression. Hyperactive TGFβ signaling perturbs DNA repair mechanisms in a manner that further weakens ICL repair in FA cells. Drugs, or classes of drugs, that target specific components of the discussed modifier pathways are shown in red.

Fig. 4

Alternate drivers of FA disease progression that are discussed in this review. The main driver of disease progression is a defect in ICL repair due to disruption of the canonical FA pathway. Impairment of a non-canonical function of an FA gene, such as autophagy, may drive the disease as well, through mechanisms that are independent of ICL repair