SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function

The methyltransferase like 3 (METTL3) is a key component of the large N-6-adenosine-methyltransferase complex in mammalian responsible for N6-methyladenosine (m(6)A) modification in diverse RNAs including mRNA, tRNA, rRNA, small nuclear RNA, microRNA precursor and long non-coding RNA. However, the characteristics of METTL3 in activation and post-translational modification (PTM) is seldom understood. Here we find that METTL3 is modified by SUMO1 mainly at lysine residues K-177, K-211, K-212 and K-215, which can be reduced by an SUMO1-specific protease SENP1. SUMOylation of METTL3 does not alter its stability, localization and interaction with METTL14 and WTAP, but significantly represses its m(6)A methytransferase activity resulting in the decrease of m(6)A levels in mRNAs. Consistently with this, the abundance of m(6)A in mRNAs is increased with re-expression of the mutant METTL3-4KR compared to that of wild-type METTL3 in human non-small cell lung carcinoma (NSCLC) cell line H1299-shMETTL3, in which endogenous METTL3 was knockdown. The alternation of m(6)A in mRNAs and subsequently change of gene expression profiles, which are mediated by SUMOylation of METTL3, may directly influence the soft-agar colony formation and xenografted tumor growth of H1299 cells. Our results uncover an important mechanism for SUMOylation of METTL3 regulating its m(6)A RNA methyltransferase activity.