Poster # 2
STABILIZATION OF ERK-PHOSPHORYLATED METTL3 BY USP5 INCREASES M6A METHYLATION
Authors: Hui-Lung Sun, UChicago; Allen C. Zhu, UChicago; Yawei Gao, Tongji University; Hideki Terajima, UChicago; Qili Fei, UChicago; Shun Liu, UChicago; Linda Zhang, UChicago; Zijie Zhang, UChicago; Bryan T. Harada, UChicago; Yu-Ying He, UChicago; Marc B. Bissonnette, UChicago; Mien-Chie Hung, China Medical University; Chuan He, UChicago
Abstract: N6-methyladenosine (m6A) is the most abundant mRNA modification, which is installed by the METTL3-METTL14-WTAP methyltransferase complex. Although the importance of m6A methylation in mRNA dynamics has been well-documented recently, the regulation of m6A machinery remains obscure. Through a genome-wide CRISPR screen, we identify the ERK pathway and USP5 as positive regulators of the m6A pathway. 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 factors 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. Overall, our study reveals an unrecognized function of ERK in regulating m6A methylation.
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