SUMOylation modification of FTO facilitates oxidative damage response of arsenic by IGF2BP3 in an m6A-dependent manner

N6-methyladenosine (m6A) is the most common form of internal post-transcriptional methylation observed in eukaryotic mRNAs. The abnormally increased level of m6A within the cells can be catalyzed by specific demethylase fat mass and obesity-associated protein (FTO) and stay in a dynamic and reversible state. However, whether and how FTO regulates oxidative damage via m6A modification remain largely unclear. Herein, by using both in vitro and in vivo models of oxidative damage induced by arsenic, we demonstrated for the first time that exposure to arsenic caused a significant increase in SUMOylation of FTO protein, and FTO SUMOylation at lysine (K)-216 site promoted the down-regulation of FTO expression in arsenic target organ lung, and therefore, remarkably elevating the oxidative damage via an m6A-dependent pathway by its specific m6A reader insulin-like growth factor-2 mRNA-binding protein-3 (IGF2BP3). Consequently, these findings not only reveal a novel mechanism underlying FTO-mediated oxidative damage from the perspective of m6A, but also imply that regulation of FTO SUMOylation may serve as potential approach for treatment of oxidative damage. Environmental Implication Arsenic is a well-known hazardous heavy metal pollutant. Exposure to arsenic can cause obvious lung injury and thereby resulting in various respiratory diseases. However, the detailed mechanisms involved remain largely unclear. Herein, we revealed for the first time that environmental-related level of arsenic exposure caused severe lung oxidative damage, which could be mediated by a m6A demethylase FTO. Intriguingly, our findings not only reveal a novel mechanism underlying FTO-mediated oxidative damage from the perspective of m6A, but also propose a new potential way for treatment of oxidative damage via regulation of FTO SUMOylation at K216 site under arsenic exposure.