SUMOylation Of The M~6A RNA Methyltransferase METTL3 Modulates Its Function

N~6-methyladenosine(m~6A)is the most common modification on RNA in eukaryotes.As the main component of m~6A methytransferase complex,METTL3 can promote N6-methyladenosine(m~6A)modification in RNA.Deletion or overexpression of METTL3 would change the RNA m~6A level,which would have effect on the decay and translation of mRNA and microRNA genesis,leading to the emergence of human disease.Though the molecular mechanisms of METTL3 in promoting RNA m~6A biogenesis is relatively known,other functions and regulations of METTL3 remain to be explored.SUMOylation(small ubiquitin-related modification)is an important and widely used reversible post-translational protein modification.Its outcomes are extremely diverse,ranging from changes in localization or the molecular interactions of the sumoylated proteins to stability of the modified protein and,in some cases,altered protein activity.Plenty of evidences by our research group and other teams show that misregulated SUMOylation may play an important role in tumor generation.In this study,we identified that METTL3 was modified by SUMO1 and K177,K211,K212 and K215 were the major SUMOylation sites of METTL3.Sequence analysis revealed that the potential sumoylation sites are highly conserved among METTL3 orthologues in different species.SUMOylation of METTL3 had little effect on its localization?protein stability and interactions with METTL14.Interestingly,we found that SUMOylation of METTL3 significantly repressed its RNA m~6A methytransferase activity.Moreover,we proved that SUMOylation of METTL3promoted colony formation and tumor growth in H1299 cells.These results suggest that SUMOylation of METTL3 is a novel molecular regulation mechanism of RNA m~6A modification.