SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function
| Autor: | Rong Deng, Jianfeng He, Jian Huang, Jianxiu Yu, Guo-Qiang Chen, Xian Zhao, Jinke Cheng, Yanming Guo, Lian Li, Ming Xu, Yanli Wang, Yuzhang Du, Bin Jiang, Jinzhuo Dou, Guofang Hou, Hailong Zhang, Ran Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adenosine SUMO protein Mice Nude Cell Cycle Proteins Biology 03 medical and health sciences microRNA Gene expression Genetics RNA and RNA-protein complexes Animals Humans RNA Messenger Messenger RNA Gene knockdown Protein Stability Lysine RNA Nuclear Proteins Sumoylation Methyltransferases Xenograft Model Antitumor Assays Cell biology 030104 developmental biology RNA methyltransferase activity RNA Splicing Factors Transcriptome Small nuclear RNA HeLa Cells |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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