2. Academic Validation
  3. Ribosome 18S m6A Methyltransferase METTL5 Promotes Translation Initiation and Breast Cancer Cell Growth

Ribosome 18S m6A Methyltransferase METTL5 Promotes Translation Initiation and Breast Cancer Cell Growth

  • Cell Rep. 2020 Dec 22;33(12):108544. doi: 10.1016/j.celrep.2020.108544.
Bowen Rong 1,  Qian Zhang 2,  Jinkai Wan 1,  Shenghui Xing 1,  Ruofei Dai 1,  Yuan Li 3,  Jiabin Cai 1,  Jiaying Xie 1,  Yang Song 1,  Jiawei Chen 4,  Lei Zhang 1,  Guoquan Yan 1,  Wen Zhang 1,  Hai Gao 1,  Jing-Dong J Han 4,  Qianhui Qu 1,  Honghui Ma 5,  Ye Tian 6,  Fei Lan 7
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Medical Epigenetics, State International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100093, China.
  • 3 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
  • 4 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing 100871, China.
  • 5 Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: honghuima@tongji.edu.cn.
  • 6 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100093, China. Electronic address: ytian@genetics.ac.cn.
  • 7 Shanghai Key Laboratory of Medical Epigenetics, State International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: fei_lan@fudan.edu.cn.
PMID: 33357433 DOI: 10.1016/j.celrep.2020.108544
Abstract

N6 methylation at adenosine 1832 (m6A1832) of mammalian 18S rRNA, occupying a critical position within the decoding center, is modified by a conserved methyltransferase, METTL5. Here, we find that METTL5 shows strong substrate preference toward the 18S A1832 motif but not the other reported m6A motifs. Comparison with a yeast ribosome structural model unmodified at this site indicates that the modification may facilitate mRNA binding by inducing conformation changes in the mammalian ribosomal decoding center. METTL5 promotes p70-S6K activation and proper translation initiation, and the loss of METTL5 significantly reduces the abundance of polysome. METTL5 expression is elevated in breast Cancer patient samples and is required for growth of several breast Cancer cell lines. We further find that Caenorhabditis elegans lacking the homolog metl-5 develop phenotypes known to be associated with impaired translation. Altogether, our findings uncover critical and conserved roles of METTL5 in the regulation of translation.

Keywords

18S; ER-UPR; METTL5; S6K; decoding center; lifespan; m6A1832; rRNA modification; ribosome; translation initiation.

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