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TRMT1 is an N2-methylguanosine (m2G) and N2,N2-methylguanosine (m22G) methyltransferase that targets G26 of both cytoplasmic and mitochondrial tRNAs. In higher eukaryotes, most cytoplasmic tRNAs with G26 carry m22G26, although the majority of mitochondrial G26-containing tRNAs carry m2G26 or G26, suggesting differences in the mechanisms by which TRMT1 catalyzes modification of these tRNAs. Loss-of-function mutations of human TRMT1 result in neurological disorders and completely abrogate tRNA:m22G26 formation. However, the mechanism underlying the independent catalytic activity of human TRMT1 and identity of its specific substrate remain elusive, hindering a comprehensive understanding of the pathogenesis of neurological disorders caused by TRMT1 mutations. Here, we showed that human TRMT1 independently catalyzes formation of the tRNA:m2G26 or m22G26 modification in a substrate-dependent manner, which explains the distinct distribution of m2G26 and m22G26 on cytoplasmic and mitochondrial tRNAs. For human TRMT1-mediated tRNA:m22G26 formation, the semi-conserved C11:G24 serves as the determinant, and the U10:A25 or G10:C25 base pair is also required, while the size of the variable loop has no effect. We defined the requirements of this recognition mechanism as the "m22G26 criteria". We found that the m22G26 modification occurred in almost all the higher eukaryotic tRNAs conforming to these criteria, suggesting the "m22G26 criteria" are applicable to other higher eukaryotic tRNAs. [ABSTRACT FROM AUTHOR]