2. Academic Validation
  3. SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function

SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function

  • Nucleic Acids Res. 2018 Jun 1;46(10):5195-5208. doi: 10.1093/nar/gky156.
Yuzhang Du 1,  Guofang Hou 1 2,  Hailong Zhang 1,  Jinzhuo Dou 1,  Jianfeng He 1,  Yanming Guo 1,  Lian Li 1,  Ran Chen 1,  Yanli Wang 1,  Rong Deng 1,  Jian Huang 1,  Bin Jiang 2,  Ming Xu 2,  Jinke Cheng 1,  Guo-Qiang Chen 3,  Xian Zhao 1,  Jianxiu Yu 1 3 4
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mohe Road, Shanghai 201999, China.
  • 3 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 4 State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
PMID: 29506078 DOI: 10.1093/nar/gky156
Abstract

The methyltransferase like 3 (METTL3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for N6-methyladenosine (m6A) 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 K177, K211, K212 and K215, 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 m6A methytransferase activity resulting in the decrease of m6A levels in mRNAs. Consistently with this, the abundance of m6A 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 m6A 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 m6A RNA methyltransferase activity.

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