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Chemical modifications of RNA have key roles in many biological processes^{, –}. N⁷-methylguanosine (m⁷G) is required for integrity and stability of a large subset of tRNAs^{, , –}. The methyltransferase 1–WD repeat-containing protein 4 (METTL1–WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types^{, , , , , –}. Mutations in WDR4 cause human developmental phenotypes including microcephaly^{, –}. How METTL1–WDR4 modifies tRNA substrates and is regulated remains elusive. Here we show,  through structural, biochemical and cellular studies of human METTL1–WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the αC region of METTL1 transforms into a helix, which together with the α6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that …