TRMT1-Catalyzed tRNA Modifications Are Required for Redox Homeostasis To Ensure Proper Cellular Proliferation and Oxidative Stress Survival
TRMT1-Catalyzed tRNA Modifications Are Required for Redox Homeostasis To Ensure Proper Cellular Proliferation and Oxidative Stress Survival
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DOI：
10.1128/mcb.00214-17
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发表时间：
2017-11-01
影响因子：
5.3
通讯作者：
Fu, Dragony
中科院分区：
文献类型：
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作者：
Dewe, Joshua M.;Fuller, Benjamin L.;Fu, Dragony
tRNA甲基转移酶1（TRMT1）基因的突变已被确定为某些形式的常染色体隐性智力残疾（ID）的原因。然而，ID相关的TRMT1突变的分子病理学是未知的，因为编码的TRMT1蛋白的生物学作用仍有待确定。在这里，我们已经阐明了TRMT1的分子靶点和功能，以揭示导致ID的TRMT1突变的细胞效应。使用人类细胞，已呈现缺乏TRMT1，我们表明，TRMT1是负责催化二甲基鸟苷（m2，2G）在核和核糖体编码的tRNA碱基修饰。TRMT1缺陷细胞表现出增殖率降低，全球蛋白质合成的改变，以及氧化还原稳态的扰动，包括内源性ROS水平增加和对氧化剂的超敏反应。值得注意的是，ID引起的TRMT1变体由于RNA结合缺陷而不能催化m2，2G的形成，并且不能挽救氧化应激敏感性。我们的研究结果揭示了TRMT1催化的tRNA修饰在氧化还原代谢中的生物学作用，并表明TRMT1相关ID的个体可能由于缺乏m2，2G修饰而对细胞内稳态产生重大干扰。
Mutations in the tRNA methyltransferase 1 (TRMT1) gene have been identified as the cause of certain forms of autosomal-recessive intellectual disability (ID). However, the molecular pathology underlying ID-associated TRMT1 mutations is unknown, since the biological role of the encoded TRMT1 protein remains to be determined. Here, we have elucidated the molecular targets and function of TRMT1 to uncover the cellular effects of ID-causing TRMT1 mutations. Using human cells that have been rendered deficient in TRMT1, we show that TRMT1 is responsible for catalyzing the dimethylguanosine (m2,2G) base modification in both nucleus-and mitochondrion-encoded tRNAs. TRMT1-deficient cells exhibit decreased proliferation rates, alterations in global protein synthesis, and perturbations in redox homeostasis, including increased endogenous ROS levels and hypersensitivity to oxidizing agents. Notably, ID-causing TRMT1 variants are unable to catalyze the formation of m2,2G due to defects in RNA binding and cannot rescue oxidative stress sensitivity. Our results uncover a biological role for TRMT1-catalyzed tRNA modification in redox metabolism and show that individuals with TRMT1-associated ID are likely to have major perturbations in cellular homeostasis due to the lack of m2,2G modifications.