METTL1 介导的 Arg-TCT tRNA 的 mG 修饰驱动致癌转化。
METTL1-mediated mG modification of Arg-TCT tRNA drives oncogenic transformation.
机构信息
Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Milner Therapeutics Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK; Storm Therapeutics Ltd., Moneta Building (B280), Babraham Research Campus, Cambridge CB22 3AT, UK.
出版信息
Mol Cell. 2021 Aug 19;81(16):3323-3338.e14. doi: 10.1016/j.molcel.2021.06.031. Epub 2021 Aug 4.
The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (mG) 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 mG-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of mG-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“转录后组学”领域正在深入研究不同 RNA 修饰的生物学和病理学作用。RNA 甲基转移酶 METTL1 催化 tRNA 的 N7-甲基鸟苷（mG）修饰。在这里，我们发现 METTL1 在癌症中经常扩增和过表达，并与患者预后不良相关。METTL1 耗竭会导致 mG 修饰的 tRNA 丰度降低，改变细胞周期并抑制致癌性。相反，METTL1 过表达会诱导致癌细胞转化和癌症。从机制上讲，我们发现 mG 修饰的 tRNA，特别是 Arg-TCT-4-1 的丰度增加，以及包括细胞周期调节剂在内的 mRNAs 的翻译增加，这些调节剂在相应的 AGA 密码子中富集。因此，Arg-TCT 在许多肿瘤类型中表达上调，并与患者的生存相关，令人惊讶的是，该单个 tRNA 的过表达会诱导致癌转化。因此，METTL1 介导的 tRNA 修饰通过重塑“翻译组”来增加促进生长的蛋白质的表达，从而驱动致癌转化，代表了一种有前途的抗癌靶点。
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