Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα.

BACKGROUND: Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche, which includes bone-forming and bone-resorbing cells, i.e., osteoblasts (OBs) and osteoclasts (OCs). OBs originate from mesenchymal progenitors, while OCs are derived from HSCs. Self-renewal, proliferation and differentiation of HSCs are under the control of regulatory signals generated by OBs and OCs within the BM niche. Consequently, OBs and OCs control both bone physiology and hematopoiesis. Since the human developmental and bone marrow failure genetic syndrome fanconi anemia (FA) presents with skeletal abnormalities, osteoporosis and HSC impairment, we wanted to test the hypothesis that the main pathological abnormalities of FA could be related to a defect in OC physiology and/or in bone homeostasis. RESULTS: We revealed here that the intrinsic differentiation of OCs from a Fanca-/- mouse is impaired in vitro due to overactivation of the p53-p21 axis and defects in NF-kB signaling. The OC differentiation abnormalities observed in vitro were rescued by treating Fanca-/- cells with the p53 inhibitor pifithrin-α, by treatment with the proinflammatory cytokine TNFα or by coculturing them with Fanca-proficient or Fanca-deficient osteoblastic cells. CONCLUSIONS: Overall, our results highlight an unappreciated role of Fanca in OC differentiation that is potentially circumvented in vivo by the presence of OBs and TNFα in the BM niche.

A new frontier in Fanconi anemia: From DNA repair to ribosome biogenesis.

Described by Guido Fanconi almost 100 years ago, Fanconi anemia (FA) is a rare genetic disease characterized by developmental abnormalities, bone marrow failure (BMF) and cancer predisposition. The proteins encoded by FA-mutated genes (FANC proteins) and assembled in the so-called FANC/BRCA pathway have key functions in DNA repair and replication safeguarding, which loss leads to chromosome structural aberrancies. Therefore, since the 1980s, FA has been considered a genomic instability and chromosome fragility syndrome. However, recent findings have demonstrated new and unexpected roles of FANC proteins in nucleolar homeostasis and ribosome biogenesis, the alteration of which impacts cellular proteostasis. Here, we review the different cellular, biochemical and molecular anomalies associated with the loss of function of FANC proteins and discuss how these anomalies contribute to BMF by comparing FA to other major inherited BMF syndromes. Our aim is to determine the extent to which alterations in the DNA damage response in FA contribute to BMF compared to the consequences of the loss of function of the FANC/BRCA pathway on the other roles of the pathway.

Fanconi anemia A protein participates in nucleolar homeostasis maintenance and ribosome biogenesis.

Fanconi anemia (FA), the most common inherited bone marrow failure and leukemia predisposition syndrome, is generally attributed to alterations in DNA damage responses due to the loss of function of the DNA repair and replication rescue activities of the FANC pathway. Here, we report that FANCA deficiency, whose inactivation has been identified in two-thirds of FA patients, is associated with nucleolar homeostasis loss, mislocalization of key nucleolar proteins, including nucleolin (NCL) and nucleophosmin 1 (NPM1), as well as alterations in ribosome biogenesis and protein synthesis. FANCA coimmunoprecipitates with NCL and NPM1 in a FANCcore complex-independent manner and, unique among the FANCcore complex proteins, associates with ribosomal subunits, influencing the stoichiometry of the translational machineries. In conclusion, we have identified unexpected nucleolar and translational consequences specifically associated with FANCA deficiency that appears to be involved in both DNA damage and nucleolar stress responses, challenging current hypothesis on FA physiopathology.