Altered transposon element-derived genes distort oxygen-free radical scavenger systems in FXD.

The altered expression of transposon element (TE)-derived genes that regulate immune responses implied the involvement of previous viral infections in the onset of Fragile X disorders (FXD), often bearing sustained inflammation. Here, we discovered that hypoxia greatly modifies the expression of TE-derived genes that act as oxygen-free radical scavengers, resulting in an alkylating environment under normoxia in FXD. Molybdenum cofactor synthesis 3 (MOCS3) and selenocysteine lyase (SCLY) stabilize the association of Kelch-like ECH-associated protein 1 (KEAP1) with PGAM family member 5 (PGAM5). This rewires connections between the oxidative stress response, cysteine-sulfur and selenium metabolism, and oxidoreductases. Desensitized tRNA thiolation against hypoxia in FXD suggests that the rewired radical scavenging system induces resistance to ROS in FXD.