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

Abstract

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.

The role of interferon‐gamma and its signaling pathway in pediatric hematological disorders

“…Moreover, it has been shown that polymorphism VNDR1349 in IFNG, which causes an increased production of IFN‐γ in vitro, is associated with an increased risk of AA 90 . Together with TNF‐α, increased levels of IFN‐γ have been found in BM of patients with Fanconi anemia, 91 an inherited BM failure syndrome 92 . However, despite the growing evidence on the possible role of IFN‐γ in AA pathogenesis, no data on the effects of in vivo inhibition of this cytokine are available.…”

Molecular pathology of rare progeroid diseases

“…ATR and CHK1 interface with the FA core complex by phosphorylation events to activate the checkpoint response (4). Downstream of ICL removal, the FA pathway recruits elements of the NER pathway and DSB repair systems homologous recombination (HR) or nonhomologous end joining (NHEJ) to resolve the lesion [96]. (C) Telomere stability depends on an intact shelterin and telomerase complex, including the reverse transcriptase TERT, the RNA template TERC, and DKC1 to protect and replicate telomeric DNA.…”

Fanconi anemia pathway and its relationship with cancer

“…FA pathway involves a bunch of FA proteins and other associated proteins, constituting a system serving for interstrand cross-link (ICL) DNA repair in the S phase (Ceccaldi et al, 2016;Milletti et al, 2020), which coordinates each critical step by interacting with various DNA damage repair (DDR) proteins (Kottemann & Smogorzewska, 2013). ICL is a special type of DNA lesions that are a covalent linkage between opposite strands of double-stranded DNA (Fig.…”