The emerging “epitranscriptomics” field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m⁷G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m⁷G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of m⁷G-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA “translatome” to increase expression of growth-promoting proteins and represents a promising anti-cancer target.

新兴的“表观转录组学”领域正在为不同 RNA 修饰的生物学和病理学作用提供见解。 RNA 甲基转移酶 METTL1 催化 tRNA 的 N7-甲基鸟苷 (m ⁷ G) 修饰。在这里，我们发现METTL1在癌症中频繁扩增和过度表达，并且与患者生存率较差有关。 METTL1 缺失会导致 m ⁷ G 修饰的 tRNA 丰度降低、细胞周期改变并抑制致癌性。相反，METTL1 过度表达会诱导致癌细胞转化和癌症。从机制上讲，我们发现 m ⁷ G 修饰的 tRNA（特别是 Arg-TCT-4-1）丰度增加，mRNA 翻译增加，包括富含相应 AGA 密码子的细胞周期调节因子。因此，Arg-TCT 表达在许多肿瘤类型中升高，并且与患者生存相关，并且引人注目的是，该个体 tRNA 的过度表达会诱导致癌转化。因此，METTL1 介导的 tRNA 修饰通过 mRNA“翻译组”的重塑来驱动致癌转化，以增加生长促进蛋白的表达，并代表了一个有前途的抗癌靶点。