Pathways to disease from natural variations in human cytoplasmic tRNAs

• Published in: The Journal of biological chemistry Vol. 294; no. 14; pp. 5294 - 5308
• Main Authors: Lant, Jeremy T., Berg, Matthew D., Heinemann, Ilka U., Brandl, Christopher J., O’Donoghue, Patrick
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.04.2019; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; cancer; Cytoplasm - genetics; Cytoplasm - metabolism; cytoplasmic tRNA; Genetic Variation; Genome, Human; human genetics; human genome; Humans; JBC Reviews; mistranslation; Neoplasms - genetics; Neoplasms - metabolism; neurodegeneration; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; nucleotide modification; Protein Biosynthesis; protein synthesis; RNA, Mitochondrial - genetics; RNA, Mitochondrial - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; RNA, Transfer - genetics; RNA, Transfer - metabolism; transfer RNA (tRNA); cytoplasmic tRNA; human genetics; transfer RNA (tRNA); nucleotide modification; neurodegeneration; human genome; protein synthesis; mistranslation; cancer
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.REV118.002982

Perfectly accurate translation of mRNA into protein is not a prerequisite for life. Resulting from errors in protein synthesis, mistranslation occurs in all cells, including human cells. The human genome encodes >600 tRNA genes, providing both the raw material for genetic variation and a buffer to ensure that resulting translation errors occur at tolerable levels. On the basis of data from the 1000 Genomes Project, we highlight the unanticipated prevalence of mistranslating tRNA variants in the human population and review studies on synthetic and natural tRNA mutations that cause mistranslation or de-regulate protein synthesis. Although mitochondrial tRNA variants are well known to drive human diseases, including developmental disorders, few studies have revealed a role for human cytoplasmic tRNA mutants in disease. In the context of the unexpectedly large number of tRNA variants in the human population, the emerging literature suggests that human diseases may be affected by natural tRNA variants that cause mistranslation or de-regulate tRNA expression and nucleotide modification. This review highlights examples relevant to genetic disorders, cancer, and neurodegeneration in which cytoplasmic tRNA variants directly cause or exacerbate disease and disease-linked phenotypes in cells, animal models, and humans. In the near future, tRNAs may be recognized as useful genetic markers to predict the onset or severity of human disease.