Analysis of Toxicant Induced Translational Control Through Codon-Usage Bias in Lung Cancer
Technical Report,01 Jul 2017,30 Jun 2018
Massachusetts Institute of Technology Cambridge United States
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The goal of this project was to test the idea that human cells respond to stress using a translational control mechanism involving changes in the levels of dozens of modified nucleosides in tRNAs, which causes selective translation of codon-biased survival genes. Here we report that exposure of human cells to oxidative stressors, including arsenic, rapidly increases the level of the wobble modification queuosine Q and one of its glycosylated derivatives, galactosyl-Q gal-Q. Exposure to alkylating agents and, ironically, ionizing radiation did not alter Q or gal-Q. Proteomics analyses revealed that proteins upregulated by arsenic were derived from genes enriched in the tyrosine codon TAC, which is read by tRNA with the anticodon gal-QUA. Among up-regulated proteins from TAC-enriched genes were those involved in glycolysis, which is consistent with the fact that arsenic uncouples oxidative phosphorylation in mitochondria. These results support a model in which cells respond to arsenic exposure by reprogramming the tRNA pool to selectively translate mRNAs from families of codon-biased genes needed to survive arsenic toxicity. These results have implications for lung cancer cells, which depend upon glycolysis as a result of the Warburg effect in tumor cells. We are now analyzing tRNA modifications and protein levels in lung cancer cells to test the idea that cancer cells are in a permanent state of codon-biased translation favoring glycolysis pathways.
- Anatomy and Physiology
- Medicine and Medical Research
- Genetic Engineering and Molecular Biology