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Transfer RNA acetylation regulates in vivo mammalian stress signaling [cells]

GSE284310 Homo sapiens Expression profiling by high throughput sequencing 6 samples Submitted 2025/02/10 Platform GPL24676
Summary
Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here, we investigate the impact of N4-acetylcytidine (ac4C), a highly conserved tRNA modification catalyzed by the essential acetyltransferase Nat10. By targeting Thumpd1, a nonessential adapter protein required for Nat10-catalyzed tRNA acetylation, we determine that loss of tRNA acetylation leads to reduced levels of tRNALeu, increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality in mice, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translational control and therapeutic interventions.
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 PRJNA1198504 and SRA study SRP551537. Searching any of these in the dataset finder brings you back here.

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