Rong Bowen, Zhang Qian, Wan Jinkai, Xing Shenghui, Dai Ruofei, Li Yuan, Cai Jiabin, Xie Jiaying, Song Yang, Chen Jiawei, Zhang Lei, Yan Guoquan, Zhang Wen, Gao Hai, Han Jing-Dong J, Qu Qianhui, Ma Honghui, Tian Ye, Lan Fei
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.
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.
Cell Rep. 2020 Dec 22;33(12):108544. doi: 10.1016/j.celrep.2020.108544.
N6 methylation at adenosine 1832 (mA1832) 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 mA 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.
哺乳动物18S rRNA腺苷1832位点（mA1832）的N6甲基化处于解码中心的关键位置，由保守的甲基转移酶METTL5修饰。在此，我们发现METTL5对18S A1832基序表现出强烈的底物偏好，而对其他已报道的mA基序则不然。与该位点未修饰的酵母核糖体结构模型比较表明，这种修饰可能通过诱导哺乳动物核糖体解码中心的构象变化来促进mRNA结合。METTL5促进p70-S6K激活和正确的翻译起始，METTL5的缺失显著降低多核糖体的丰度。METTL5在乳腺癌患者样本中的表达升高，并且是几种乳腺癌细胞系生长所必需的。我们进一步发现，缺乏同源物metl-5的秀丽隐杆线虫会出现已知与翻译受损相关的表型。总之，我们的发现揭示了METTL5在翻译调控中的关键和保守作用。
