Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

Simple Summary Fanconi anemia (FA) is a genetic disorder that is characterized by bone marrow failure (BMF), developmental abnormalities, and predisposition to cancer. In this review, we present an overview of both canonical (regulation of interstrand cross-links repair, ICLs) and noncanonical roles of FA proteins. We divide noncanonical alternative functions in two types: nuclear (outside ICLs such as FA action in replication stress or DSB repair) and cytosolic (such as in mitochondrial quality control or selective autophagy). We further discuss the involvement of FA genes in the predisposition to develop different types of cancers and we examine current DNA damage response-targeted therapies. Finally, we promote an insightful perspective regarding the clinical implication of the cytosolic noncanonical roles of FA proteins in cancer predisposition, suggesting that these alternative roles could be of critical importance for disease progression. Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches.