TRMT1L-Catalyzed m22G27 on Tyrosine tRNA Is Required for Efficient mRNA Translation and Cell Survival Under Oxidative Stress

Authors

Sseu-Pei Hwang
Han Liao
Katherine Barondeau
Xinyi Han
Cassandra Herbert
Hunter McConie
Amirtha Shekar
Dimitri G Pestov
Patrick A Limbach
Jeffrey T Chang
Catherine Denicourt

Publication Date

1-28-2025

Journal

Cell Reports

Abstract

tRNA modifications are critical for several aspects of their functions, including decoding, folding, and stability. Using a multifaceted approach encompassing eCLIP-seq and nanopore tRNA-seq, we show that the human tRNA methyltransferase TRMT1L interacts with the component of the Rix1 ribosome biogenesis complex and binds to the 28S rRNA as well as to a subset of tRNAs. Mechanistically, we demonstrate that TRMT1L is responsible for catalyzing N2,N2-dimethylguanosine (m22G) solely at position 27 of tRNA-Tyr-GUA. Surprisingly, TRMT1L depletion also impaired the deposition of 3-(3-amino-3-carboxypropyl) uridine (acp3U) and dihydrouridine on tRNA-Tyr-GUA, Cys-GCA, and Ala-CGC. TRMT1L knockout cells have a marked decrease in tRNA-Tyr-GUA levels, coinciding with a reduction in global translation rates and hypersensitivity to oxidative stress. Our results establish TRMT1L as the elusive methyltransferase catalyzing the m22G27 modification on tRNA Tyr, resolving a long-standing gap of knowledge and highlighting its potential role in a tRNA modification circuit crucial for translation regulation and stress response.

Keywords

Humans, Oxidative Stress, Protein Biosynthesis, tRNA Methyltransferases, Cell Survival, RNA, Messenger, HEK293 Cells, RNA, Transfer, Guanosine

DOI

10.1016/j.celrep.2024.115167

PMID

39786998

PMCID

PMC11834103

PubMedCentral® Posted Date

2-18-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes