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.

Keywords: DNA damage; Fanconi anemia; RIG-I; cGAS/STING; cytosolic DNA; inflammation; interferon.

Figure 1

Schematic representation of ICLs repair by the Fanconi Anemia pathway. The protein complex composed of FANCM-MHF1-MHF2 is recruited to the chromatin upon recognition of ICL damage. Then, FANCM is activated and allows the recruitment of the core complex of the FA pathway composed of: FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FAAP100, FAAP20 and FAAP24. The core complex contains an ubiquitin E3 ligase activity and is responsible for the monoubiquitylation of the ID2 complex composed of FANCI and FANCD2 proteins. Monoubiquitinylation of ID2 complex promotes the recruitment of the nucleases FANP, FANCQ and FAN1 and end resection at the DNA damage site. Depending on the cellular context, recruitment of downstream factors belonging to either Homologous Recombination (HR) or to Non-homologous End Joining (NHEJ) will finalize the repair.

Figure 2

Proposed model depicting how defect in the FA pathway could induce pathological IFN-I production. FA proteins prevent genome instability by repairing DNA damage, repressing retrotransposition and allowing accurate cell division. In addition, FA proteins modulate anti-oxidative response and participate in mitochondria clearance by autophagy and mitophagy processes. Mutations in FA genes or loss of FA proteins contribute to DNA damage accumulation, genome instability, reactive oxygen species (ROS) production and defect in mitochondria’s clearance. Under these pathological conditions, many types of self-nucleic acids such as ssDNA and dsDNA (A), micronuclei (B) chromatin bridges (C) retroelements (RTE) and R-loops (D), mtDNA/RNA (E), can activate type-I Interferon (IFN-I). This would occur by cGAS and RIG-I detection of cytosolic DNA and RNA molecules respectively and subsequent production of IFN-I. In addition, elevated levels of ROS might contribute to fuel the production of IFN-I by creating more DNA and mitochondria damage (F).