A never-ending story: the steadily growing family of the FA and FA-like genes

Abstract

Among the chromosome fragility-associated human syndromes that present cancer predisposition, Fanconi anemia (FA) is unique due to its large genetic heterogeneity. To date, mutations in 21 genes have been associated with an FA or an FA-like clinical and cellular phenotype, whose hallmarks are bone marrow failure, predisposition to acute myeloid leukemia and a cellular and chromosomal hypersensitivity to DNA crosslinking agents exposure. The goal of this review is to trace the history of the identification of FA genes, a history that started in the eighties and is not yet over, as indicated by the cloning of a twenty-first FA gene in 2016.

SMC5/6 acts jointly with Fanconi anemia factors to support DNA repair and genome stability

“…So far, 22 complementation groups have been delineated in FA, with the causal genes shown to act in a common repair pathway [35][36][37]. So far, 22 complementation groups have been delineated in FA, with the causal genes shown to act in a common repair pathway [35][36][37].…”

A journey with common fragile sites: From S phase to telophase

“…Patients present several pathological traits, including developmental abnormalities, hematological failure, high risk of leukemia, and hypofertility . On the basis of the key characteristics of cells derived from the FA patients, including chromosomal fragility and hypersensitivity to DNA crosslinking agents, at least 21 genes and cognate proteins have been associated to FA or a FA‐like phenotype . However, cellular, genetics, molecular, biochemical, and functional studies have extended the list to incorporate more than two dozens of new proteins in which loss‐of‐function has been retrieved in at least one patient presenting the clinical stigmata of FA.…”

“…Monoubiquitination allows association of FANCD2 and FANCI and their localization in subnuclear foci on damaged DNA or at stalled/delayed replication forks, including at CFSs . The third module of the FANC pathway is composed of proteins involved in homologous recombination . In a cooperative relationship, the optimal activation/activity of both the first and the second FANC modules is ATR signaling dependent and, in turn, FANCM participates to optimal ATR activation.…”

“…32,33 The third module of the FANC pathway is composed of proteins involved in homologous recombination. 18,30 In a cooperative relationship, the optimal activation/activity of both the first and the second FANC modules is ATR signaling dependent and, in turn, FANCM participates to optimal ATR activation. Indeed, ATR activation and replication fork restart are defective in FANCM-deficient cells.…”

Fanconi anemia proteins are required to maintain nucleolar homeostasis

“…FA is the most frequent and genetically heterogeneous iBMF syndrome (Bogliolo and Surralles, 2015;Ceccaldi et al, 2016;Gueiderikh et al, 2017), and is associated with developmental abnormalities, predisposition to cancer and chromosomal instability. The key function of the molecular pathway defined by FA proteins (FANC) is to resolve DNA interstrand crosslinks (ICLs) and stalled replication forks that can arise from endogeneous aldheyde metabolism or following exposure to ICL-inducing agents, as mitomycin C, cis-Pt or photoactivated psoralens (Bogliolo and Surralles, 2015;Ceccaldi et al, 2016;Gueiderikh et al, 2017;Langevin et al, 2011;Rosado et al, 2011). The FANC proteins are organized in three distinct functional groups.…”