Type-I Interferon Signaling in Fanconi Anemia

Abstract

Fanconi Anemia (FA) is a genome instability syndrome caused by mutations in one of the 23 repair genes of the Fanconi pathway. This heterogenous disease is usually characterized by congenital abnormalities, premature ageing and bone marrow failure. FA patients also show a high predisposition to hematological and solid cancers. The Fanconi pathway ensures the repair of interstrand crosslinks (ICLs) DNA damage. Defect in one of its proteins prevents functional DNA repair, leading to the accumulation of DNA breaks and genome instability. Accumulating evidence has documented a close relationship between genome instability and inflammation, including the production of type-I Interferon. In this context, type-I Interferon is produced upon activation of pattern recognition receptors by nucleic acids including by the cyclic GMP-AMP synthase (cGAS) that detects DNA. In mouse models of diseases displaying genome instability, type-I Interferon response is responsible for an important part of the pathological symptoms, including premature aging, short stature, and neurodegeneration. This is illustrated in mouse models of Ataxia-telangiectasia and Aicardi-Goutières Syndrome in which genetic depletion of either Interferon Receptor IFNAR, cGAS or STING relieves pathological symptoms. FA is also a genetic instability syndrome with symptoms such as premature aging and predisposition to cancer. In this review we will focus on the different molecular mechanisms potentially leading to type-I Interferon activation. A better understanding of the molecular mechanisms engaging type-I Interferon signaling in FA may ultimately lead to the discovery of new therapeutic targets to rescue the pathological inflammation and premature aging associated with Fanconi Anemia.

Two siblings with Fanconi anemia (FANCQ, ERCC4/XPF) presenting with tumor‐mimicking lesions in the brain and acute neurological deterioration

“…6 Evidence suggests that FA is also caused by the cGAS-STING pathway of IFN-I. 5 It is unknown whether defects in each of the 23 FA genes yield similar outcomes for IFN-I. This loss of function in these genes (FANC-D,J,N,O,P,Q,R,S,T,U,V,W, and Y) results in self-DNA accumulation, cGAS activation is facilitated and IFN-I synthesis is stimulated.…”

“…This loss of function in these genes (FANC-D,J,N,O,P,Q,R,S,T,U,V,W, and Y) results in self-DNA accumulation, cGAS activation is facilitated and IFN-I synthesis is stimulated. 5 The IFN-I response stimulates the immune system, thereby causing hyperin-…”

Research progress on the fanconi anemia signaling pathway in non-obstructive azoospermia

“…Embryonic stem cells can differentiate into germ cells, so blocking the FNACG signaling pathway may reduce the number of sperm in mice ( 117 – 119 ). In addition, exogenous stimuli such as cisplatin and mitomycin C lead to the production of cellular ICL, where the FA protein recognizes and repairs damaged DNA or excises faulty coding ( 120 ). When the FA gene is missing, the damaged DNA accumulates in the cell, The resulting self-nucleic acids activate the cyclic GMP-AMP synthase (cGAS) in the cytoplasm to produce secondary messenger cGAMP, which in turn activates type I interferons (IFN-I), which is involved in the emergence of Fanconi related disease phenotypes via the cGAS-STING-IFN-I axis ( 120 , 121 ).…”

The role of inflammation in hematopoiesis and bone marrow failure: What can we learn from mouse models?

“…Hence, the different animal models developed in the recent years regarding immune-related mechanisms ( 61 – 63 ) and hematopoiesis have helped to understand the pathogenesis of the different congenital and acquired BM failure syndromes ( 64 – 67 ) and might yield further insights into the development of novel therapeutic strategies that will target or even prevent hematopoietic failure in these syndromes.…”