Analysis of Toxicant Induced Translational Control Through Codon-Usage Bias in Lung Cancer
Abstract
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-Q)UA. 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2018
- Accession Number
- AD1095972
Entities
People
- Ahmed Fazly
- Peter Dedon
Organizations
- Massachusetts Institute of Technology