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).