生物
翻译(生物学)
癌变
信使核糖核酸
甲基化
遗传学
DNA甲基化
延伸率
计算生物学
细胞生物学
分子生物学
基因
基因表达
材料科学
极限抗拉强度
冶金
作者
Joel William Francis,Simone Hausmann,Sabeen Ikram,Kunlun Yin,Robert Mealey-Farr,Natasha Flores,Anhthu Trinh,Tourkian Chasan,Jane L. Thompson,Paweł K. Mazur,Or Gozani
标识
DOI:10.1016/j.molcel.2024.02.037
摘要
eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression of the FAM86A-eEF2K525me3 axis inhibits cancer cell and patient-derived LUAD xenograft growth in vivo. Finally, FAM86A ablation strongly attenuates tumor growth and extends survival in KRASG12C-driven LUAD mouse models. Thus, our work uncovers an eEF2 methylation-mediated mRNA translation elongation regulatory node and nominates FAM86A as an etiologic agent in LUAD.
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