The genomic loci of specific human tRNA genes exhibit ageing-related DNA hypermethylation

Journal article

tRNAs are evolutionarily ancient molecular decoders essential for protein translation. In eukaryotes, tRNAs and other short, noncoding RNAs are transcribed by RNA polymerase (Pol) III, an enzyme that promotes ageing in yeast, worms, and flies. Here, we show that a partial reduction in Pol III activity specifically disrupts tRNA levels. This effect is conserved across worms, flies, and mice, where computational models indicate that it impacts mRNA decoding. In all 3 species, reduced Pol III activity increases proteostatic resilience. In worms, it activates the unfolded protein response (UPR) and direct disruption of tRNA metabolism is sufficient to recapitulate this. In flies, decreasing Pol III’s transcriptional initiation on tRNA genes by a loss-of-function in the TFIIIC transcription factor robustly extends lifespan, improves proteostatic resilience and recapitulates the broad-spectrum benefits to late-life health seen following partial Pol III inhibition. We provide evidence that a partial reduction in Pol III activity impacts translation, quantitatively or qualitatively, in both worms and flies, indicating a potential mode of action. Our work demonstrates a conserved and previously unappreciated role of tRNAs in animal ageing

Authors: Acton, RJ; Yuan, W; Gao, F; Xia, Y; Bourne, E

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 12
• Issue: 1
• Pages: 2655-2655
• Article number: 2655
• Publication date: 2021-05-11
• DOI: 10.1038/s41467-021-22639-6
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Methylated DNA immunoprecipitation; Genetics; Epigenetics; DNA methylation; Computational biology; Transfer RNA; Methylation; Gene expression; Human genome; Genome; Epigenome; Gene; genomic DNA; RNA; Biology