tRNA Deregulation and Its Consequences in Cancer

tRNAs are positively regulated by oncogenes, often being increased in several types of cancer in a tissue-dependent manner, although individual regulation still lacks understanding. Upregulation of specific tRNAs stabilizes transcripts that can be responsible for inducing cancer hallmarks, such as metastasis. tRNA sets are valuable yet still unexplored biomarkers, which can be used to discriminate tumors from normal tissue and to predict patient outcome. tRNA deregulation induces protein synthesis errors, which have been correlated to accelerated tumor growth kinetics. Increased protein errors produced by tRNA imbalance induce cellular reprogramming to mitigate stress, becoming a source of population heterogeneity. The expression of transfer RNAs (tRNAs) is deregulated in cancer cells but the mechanisms and functional meaning of such deregulation are poorly understood. The proteome of cancer cells is not fully encoded by their transcriptome, however, the contribution of mRNA translation to such diversity remains to be elucidated. We review data supporting the hypothesis that tRNA expression deregulation and translational error rate is an important contributor to proteome diversity and cell population heterogeneity, genome instability, and drug resistance in tumors. This hypothesis is aligned with recent data in various model organisms, showing unanticipated adaptive roles of translational errors (adaptive mistranslation), expression control of specific gene subsets by tRNAs, and proteome diversification by elevation of translational error rates in tumors. The expression of transfer RNAs (tRNAs) is deregulated in cancer cells but the mechanisms and functional meaning of such deregulation are poorly understood. The proteome of cancer cells is not fully encoded by their transcriptome, however, the contribution of mRNA translation to such diversity remains to be elucidated. We review data supporting the hypothesis that tRNA expression deregulation and translational error rate is an important contributor to proteome diversity and cell population heterogeneity, genome instability, and drug resistance in tumors. This hypothesis is aligned with recent data in various model organisms, showing unanticipated adaptive roles of translational errors (adaptive mistranslation), expression control of specific gene subsets by tRNAs, and proteome diversification by elevation of translational error rates in tumors. novel characteristics induced in tumor cells by the treatment that allows them to resist to this same drug treatment. errors in protein synthesis that help to establish advantageous features. natural process where specific exons of a precursor mRNA are included or not in the mature mRNA. Proteins translated from alternatively spliced mRNAs will differ in their sequence and, often, in their biological functions. enzymes that attach the cognate amino acids to tRNAs. There is one aaRS for each amino acid. a three-nucleotide sequence present in tRNAs that is complementary to mRNA codon and allows the decoding of genetic information into amino acids. nucleotide in position 34 which pairs with the third mRNA codon base during ribosome decoding. Codon–anticodon pairing in this position is looser due to modifications in this nucleotide, which expand tRNA ability to decode multiple mRNA codons differing in the third position. intracellular degradation system by which cytoplasmic materials, including proteins, are degraded in the lysosome. biological abilities acquired during tumor development, including: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. most amino acids are encoded by several synonymous codons. These codons are not used with the same frequency and highly expressed genes tend to be enriched in codons that match the tRNA pool. This codon usage bias has been associated with increased translation accuracy, efficiency, modulation of translation speed, protein folding, and stability of secondary structures. tRNA matching the codon in the mRNA or an amino acid. catalytic subunit of large enzymatic complexes that acetylate specific lysine residues on histone tails to promote transcriptional activation. pre-existing characteristics of cancer cells that confer insensibility to drug treatments. small, highly conserved non-coding RNA molecules involved in gene expression regulation. improper attachment of an amino acid to a non-cognate tRNA. chemically similar tRNA to the one matching the codon in the mRNA or an amino acid. cells which have lost the ability to divide. tRNAs isoforms that are charged with the same amino acid. process where a tRNA reads a non-cognate codon, inducing the incorporation of a wrong amino acid in a protein. one of the major cellular protein degradation systems. cellular stress response triggered by accumulation of misfolded proteins in the endoplasmic reticulum. nucleotides which pair according to Watson-Crick rules: adenine (A) binds to thymine (T) in DNA molecules or uracyl (U) in RNA molecules and guanine (G) binds to cytosine (C).