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Transfer RNA acetylation regulates in vivo mammalian stress signaling

GSE311268 Homo sapiens Expression profiling by high throughput sequencing 4 samples Submitted 2025/11/27 Platform GPL30882
Summary
Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their physiological roles remain poorly understood. Here we investigate the impact of N4-acetylcytidine (ac4C), a highly conserved tRNA modification, using a Thumpd1 knockout mouse model. We find that loss of Thumpd1-dependent tRNA acetylation leads to reduced levels of tRNALeu , increased ribosome stalling and collisions, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Remarkably, concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality, revealing a critical genetic interaction. Our findings demonstrate that a modification restricted to a single site within type II cytosolic tRNAs can regulate ribosome-mediated signaling in mammalian organisms. By providing insight into how tRNA modifications shape signaling and cell fate in response to stress, this work opens up novel strategies for therapeutic intervention and translational control.
Published in
Transfer RNA acetylation regulates in vivo mammalian stress signaling
Thalalla Gamage S, Khoogar R, Howpay Manage S et al. · Science advances 2025 · PMID 40106564 · doi:10.1126/sciadv.ads2923
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Also filed as BioProject PRJNA1368865 and SRA study SRP648485. Searching any of these in the dataset finder brings you back here.

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