TY - JOUR
T1 - Mutation bias within oncogene families is related to proliferation-specific codon usage
AU - Benisty, Hannah
AU - Weber, Marc
AU - Hernandez-Alias, Xavier
AU - Schaefer, Martin H.
AU - Serrano, Luis
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Eva Maria Novoa and Manuel Irimia for stimulating and critical discussions. We thank Disa Tehler for providing BJ/ hTERT cells. We would also like to thank Tony Ferrar for scientific and language editing. The work of X.H.-A. has been supported by a PhD fellowship from the Fundación Ramón Areces. We acknowledge the support of the Spanish Ministry of Science and Innovation to the European Molecular Biology Laboratory partnership, the Centro de Excelencia Severo Ochoa and the Centres de Recerca de Catalunya Programme/Generalitat de Catalunya.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - Codon usage
KW - KRAS
KW - Oncogene
KW - Translation
KW - TRNA
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U2 - 10.1073/pnas.2016119117
DO - 10.1073/pnas.2016119117
M3 - Article
C2 - 33199641
AN - SCOPUS:85097211082
VL - 117
SP - 30848
EP - 30856
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 48
ER -