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Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs
Author(s) -
Li Jing,
Wang YanNan,
Xu BeiSi,
Liu YaPing,
Zhou Mi,
Long Tao,
Li Hao,
Dong Han,
Nie Yan,
Chen Peng R,
Wang EnDuo,
Liu RuJuan
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050095
Subject(s) - transfer rna , biology , methylation , genetics , gene , rna , translation (biology) , mutation , methyltransferase , rna editing , messenger rna
tRNA modifications at the anti‐codon loop are critical for accurate decoding. FTSJ1 was hypothesized to be a human tRNA 2′‐O‐methyltransferase. tRNA Phe (GAA) from intellectual disability patients with mutations in ftsj1 lacks 2′‐O‐methylation at C32 and G34 (Cm32 and Gm34). However, the catalytic activity, RNA substrates, and pathogenic mechanism of FTSJ1 remain unknown, owing, in part, to the difficulty in reconstituting enzymatic activity in vitro . Here, we identify an interacting protein of FTSJ1, WDR6. For the first time, we reconstitute the 2′‐O‐methylation activity of the FTSJ1‐WDR6 complex in vitro , which occurs at position 34 of specific tRNAs with m 1 G37 as a prerequisite. We find that modifications at positions 32, 34, and 37 are interdependent and occur in a hierarchical order in vivo . We also show that the translation efficiency of the UUU codon, but not the UUC codon decoded by tRNA Phe (GAA), is reduced in ftsj1 knockout cells. Bioinformatics analysis reveals that almost 40% of the high TTT‐biased genes are related to brain/nervous functions. Our data potentially enhance our understanding of the relationship between FTSJ1 and nervous system development.