Copy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation

Laetitia A. Hughes, Danielle L. Rudler, Stefan J. Siira, Tim McCubbin, Samuel A. Raven, Jasmin M. Browne, Judith A. Ermer, Jeanette Rientjes, Jennifer Rodger, Esteban Marcellin, Oliver Rackham () and Aleksandra Filipovska ()
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Laetitia A. Hughes: Harry Perkins Institute of Medical Research
Danielle L. Rudler: Harry Perkins Institute of Medical Research
Stefan J. Siira: Harry Perkins Institute of Medical Research
Tim McCubbin: The University of Queensland
Samuel A. Raven: Harry Perkins Institute of Medical Research
Jasmin M. Browne: Harry Perkins Institute of Medical Research
Judith A. Ermer: Harry Perkins Institute of Medical Research
Jeanette Rientjes: Monash University
Jennifer Rodger: The University of Western Australia
Esteban Marcellin: QEII Medical Centre
Oliver Rackham: Harry Perkins Institute of Medical Research
Aleksandra Filipovska: Harry Perkins Institute of Medical Research

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract The number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-Seq, RNA-seq, ribo-profiling and proteomics we observed distinct molecular consequences of single tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoder genes buffer the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least six tRNA-Phe alleles is required for embryonic viability and tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA genes is required to buffer translation and viability in mammals.

Date: 2023
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DOI: 10.1038/s41467-023-37843-9

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