Hernandez-Alias, X. | bioRxiv Science

bioRxiv2019

Translational efficiency across healthy and tumor tissues is proliferation-related

BackgroundDifferent tissues express genes with particular codon usage and anticodon tRNA repertoires. However, the codon-anticodon co-adaptation in humans is not completely understood, as well as its effect on tissue-specific protein levels.\n\nResultsWe first validated the accuracy of small RNA-seq for tRNA quantification across five human cell lines. We then analyzed tRNA expression in more than 8000 tumor samples from TCGA, together with their paired mRNA-seq and proteomics data, to determine the Relative Translation Efficiency. We thereby elucidate that the dynamic adaptation of the tRNA pool is largely related to the proliferative state across tissues, which determines tissue-specific translation efficiency. Furthermore, the aberrant translational efficiency of ProCCA and GlyGGT in cancer, among other codons, which is partly regulated by the tRNA gene copy numbers and their promoter DNA methylation, is associated with poor patient survival.\n\nConclusionsThe distribution of tissue-specific tRNA pools over the whole cellular translatome affects the subsequent translational efficiency, which functionally determines a condition-specific expression program in tissues both in healthy and tumor states.

systems biology↗

bioRxiv2019

Proliferation specific codon usage facilitates oncogene translation

Tumors evolve under selection for gene mutations that give a growth advantage to the cancer cell. Intriguingly, some cancer genes are more often found mutated in tumors than their closely related family members. For example, KRAS mutations are more frequently observed in cancer in comparison to HRAS and NRAS. Here, we find that for RAS and six oncogene families, the most prevalent mutated members in cancer have a codon usage characteristic of genes involved in proliferation. The codon usage of KRAS is more adapted to be efficiently translated in proliferative cells than the codon usage of HRAS. We also show that the translation efficiency of KRAS varies between cell lines in a manner related to their tRNA expression. Altogether, our study demonstrates that a dynamic translation program contributes to shaping the expression profiles of oncogenes. We propose that codon bias related to cell proliferation contributes to the prevalence of mutations in certain members of oncogene families.

cancer biology↗