生物
MAPK/ERK通路
细胞生物学
磷酸化
甲基化
癌变
胚胎干细胞
表观遗传学
甲基转移酶
遗传学
N6-甲基腺苷
癌症
基因
作者
Hui‐Lung Sun,Allen Zhu,Yawei Gao,Hideki Terajima,Qili Fei,Shun Liu,Linda Zhang,Zijie Zhang,Bryan T. Harada,Yu‐Ying He,Marc Bissonnette,Mien‐Chie Hung,Chuan He
出处
期刊:Molecular Cell
[Elsevier]
日期:2020-11-01
卷期号:80 (4): 633-647.e7
被引量:78
标识
DOI:10.1016/j.molcel.2020.10.026
摘要
N6-methyladenosine (m6A) is the most abundant mRNA modification and is installed by the METTL3-METTL14-WTAP methyltransferase complex. Although the importance of m6A methylation in mRNA metabolism has been well documented recently, regulation of the m6A machinery remains obscure. Through a genome-wide CRISPR screen, we identify the ERK pathway and USP5 as positive regulators of the m6A deposition. We find that ERK phosphorylates METTL3 at S43/S50/S525 and WTAP at S306/S341, followed by deubiquitination by USP5, resulting in stabilization of the m6A methyltransferase complex. Lack of METTL3/WTAP phosphorylation reduces decay of m6A-labeled pluripotent factor transcripts and traps mouse embryonic stem cells in the pluripotent state. The same phosphorylation can also be found in ERK-activated human cancer cells and contribute to tumorigenesis. Our study reveals an unrecognized function of ERK in regulating m6A methylation.
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