RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis
RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis
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DOI：
10.1038/nsmb.2357
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发表时间：
2012-09-01
影响因子：
16.8
通讯作者：
Lyko, Frank
中科院分区：
文献类型：
--
作者：
Tuorto, Francesca;Liebers, Reinhard;Lyko, Frank
胞嘧啶-C5甲基化是一种广泛的tRNA修饰，其功能仍然不清楚，特别是在哺乳动物中。我们现在已经通过破坏Dnmt 2和NSun 2 tRNA甲基转移酶开发了胞嘧啶-C5 tRNA甲基化缺陷的小鼠品系。虽然缺乏任何一种酶单独对小鼠的生存能力没有可检测的影响，双突变体显示出合成的致命的相互作用，与不发达的表型和受损的细胞分化。对双敲除小鼠的tRNA甲基化分析表明，Dnmt 2和NSun 2具有互补的靶位点特异性，胞嘧啶-C5 tRNA甲基化完全丧失。未甲基化的tRNA的稳态水平显著降低，Dnmt 2和NSun 2的丢失进一步与整体蛋白质合成速率降低相关。这些结果建立了哺乳动物中胞嘧啶-C5 tRNA甲基化的生物学重要功能，并表明这种修饰通过支持蛋白质合成促进小鼠发育。
The function of cytosine-C5 methylation, a widespread modification of tRNAs, has remained obscure, particularly in mammals. We have now developed a mouse strain defective in cytosine-C5 tRNA methylation, by disrupting both the Dnmt2 and the NSun2 tRNA methyltransferases. Although the lack of either enzyme alone has no detectable effects on mouse viability, double mutants showed a synthetic lethal interaction, with an underdeveloped phenotype and impaired cellular differentiation. tRNA methylation analysis of the double-knockout mice demonstrated complementary target-site specificities for Dnmt2 and NSun2 and a complete loss of cytosine-C5 tRNA methylation. Steady-state levels of unmethylated tRNAs were substantially reduced, and loss of Dnmt2 and NSun2 was further associated with reduced rates of overall protein synthesis. These results establish a biologically important function for cytosine-C5 tRNA methylation in mammals and suggest that this modification promotes mouse development by supporting protein synthesis.