PDF(Sci-hub)
Abstract：
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.
摘要：
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障碍（ID）的原因。然而,ID相关TRMT1突变的分子病理学未知，因为编码的TRMT1蛋白的生物学作用仍有待确定。这里,我们已经阐明了TRMT1的分子靶标和功能,以揭示引起ID的TRMT1突变的细胞效应.使用已变得缺乏TRMT1的人类细胞，我们显示TRMT1负责催化细胞核和线粒体编码的tRNA中的二甲基鸟苷（m2,2G）碱基修饰。TRMT1缺陷细胞表现出降低的增殖率，整体蛋白质合成的改变，和氧化还原稳态的扰动，包括内源性ROS水平增加和对氧化剂过敏。值得注意的是,引起ID的TRMT1变体由于RNA结合中的缺陷而不能催化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，并表明具有TRMT1相关ID的个体由于缺乏m2,2G修饰而可能在细胞稳态中具有重大扰动。
