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Elucidating the human tRNA transcriptome dependent upon the TRMT1 and TRMT1L paralogs for modification, stability, and function

ABSTRACT: The tRNA methyltransferase 1 (TRMT1) enzyme catalyzes the formation of dimethylguanosine (m2,2G) in tRNAs. Loss-of-function mutations in TRMT1 lead to intellectual disability disorders in humans. In addition to TRMT1, vertebrates encode a tRNA methyltransferase 1-like (TRMT1L) paralog. Here, we use a comprehensive tRNA sequencing approach to decipher the landscape of tRNAs that are modified by human TRMT1 and TRMT1L. We find that TRMT1 modifies a single position in more than half of all cytoplasmic tRNAs and a subset of mitochondrial tRNAs. Notably, TRMT1 and TRMT1L catalyze m2,2G formation at distinct positions in tyrosine tRNAs that are each required for the efficient installation of additional modifications. Moreover, we identify a role for m2,2G modification in the stability of tyrosine and serine tRNAs that is abrogated in human patient cells homozygous for pathogenic TRMT1 variants. Human cells deficient in TRMT1 and/or TRMT1L exhibit reduced translation of specific codons, indicating that m2,2G modifications are necessary for maintaining functional levels of certain tRNAs. These findings uncover key roles for the m2,2G modification, and pinpoint tRNAs that are dysregulated in neurodevelopmental disorders caused by tRNA modification deficiency.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263642 | GEO | 2024/08/09

REPOSITORIES: GEO

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