Mutation bias within oncogene families is related to proliferation-specific codon usage
Menée à partir de données génétiques issues de plusieurs sources (Projet TGCA, AmiGO, ...), cette étude analyse la relation entre la fréquence des mutations au sein d'une même famille d'oncogènes, l'utilisation des codons et l'oncogénicité
Résumé en anglais
In light of the genetic code, combinations of three nucleotides which are known as synonymous codons, can give rise to the same amino acid. Despite the homology at the protein level, these different codons are recognized distinctly by the translational machinery. The unequal use of synonymous codons influences protein expression. Surprisingly, we find that the coding sequences of KRAS and other frequently mutated cancer genes are adapted to be efficiently translated in proliferating cells in comparison to their family counterparts. Our work contributes to the unsolved question of why in tumors some members of cancer gene families show a higher mutation rate than their family counterparts. Thus, our results elucidate the relationship between tRNA expression, codon usage, and oncogenicity.
It is well known that in cancer gene families some members are more frequently mutated in tumor samples than their family counterparts. A paradigmatic case of this phenomenon is KRAS from the RAS family. Different explanations have been proposed ranging from differential interaction with other proteins to preferential expression or localization. Interestingly, it has been described that despite the high amino acid identity between RAS family members, KRAS employs an intriguing differential codon usage. Here, we found that this phenomenon is not exclusive to the RAS family. Indeed, in the RAS family and other oncogene families with two or three members, the most prevalently mutated gene in tumor samples employs a differential codon usage that is characteristic of genes involved in proliferation. Prompted by these observations, we chose the RAS family to experimentally demonstrate that the translation efficiency of oncogenes that are preferentially mutated in tumor samples is increased in proliferative cells compared to quiescent cells. These results were further validated by assessing the translation efficiency of KRAS in cell lines that differ in their tRNA expression profile. These differences are related to the cell division rate of the studied cells and thus suggest an important role in context-specific oncogene expression regulation. Altogether, our study demonstrates that dynamic translation programs contribute to shaping the expression profiles of oncogenes. Therefore, we propose this codon bias as a regulatory layer to control cell context-specific expression and explain the differential prevalence of mutations in certain members of oncogene families.All data generated during this study are included in this published article and its SI Appendix. Sequencing data generated during this study have been deposited in ArrayExpress database (54) under accession number E-MTAB-8144. BJ/hTERT sequencing data are available from Gene Expression Omnibus (55) under the accession code GSE137834 (56). All TCGA data (57) are available for download through the Genomic Data Commons Data Portal (https://portal.gdc.cancer.gov/). Codon usage of oncogenes and tRNA mapping are reported in the GitHub repository: https://github.com/webermarcolivier/codon_usage_oncogenes; https://github.com/hexavier/tRNA_mapping.
