The regulation, function and disease relevance of cytoplasmic tRNAs

Transfer RNAs (tRNAs) are core components of protein synthesis. Recent studies and technological advances have expanded our understanding of the complexities of tRNA biology. In this Review, we discuss the genomic organization and spatiotemporal expression of human cytoplasmic tRNAs, the quality control pathways that govern their maturation and functionality, and how dysregulation of tRNA biogenesis and function contributes to human pathologies. We also present emerging concepts regarding how tissue-specific tRNA abundance regulates translation velocity and how tRNAs are centrally involved in surveillance and stress signalling pathways, including ribosome-associated quality control and the integrated stress response. We further discuss the potential of tRNA-based therapeutics, highlighting new strategies to address tRNA-associated translation defects. By bridging between molecular tRNA biology and its clinical implications, we emphasize the crucial need to understand the intricacies of tRNA regulation in order to therapeutically target them in a variety of diseases.