A central tenet of biology is the accurate flow of information from nucleic acids to proteins through the genetic code. It is commonly believed that translation deviating from the genetic code is to be avoided at all times in cells. By using a new genomic method, we have discovered that in contrary, mammalian cells can deliberately reprogram the genetic code with the amino acid methionine upon innate immune activation and chemically triggered oxidative stress. Reprogramming the genetic code occurs through aminoacylation of non-methionyl-tRNAs with methionine, and is inducible upon regulated production of the reactive oxygen species (ROS) in the cell. We propose that mis-translation via regulated tRNA misacylation is a common mechanism for stress response for cells. We will explore and test hypotheses on biological effects and function on tRNA misacylation with methionine and establish a full spectrum of tRNA misacylation for all amino acids and their participations in translation in mammalian cells. The results and conceptual understanding obtained here shall help establish a new field of biology of mis-translation.

Public Health Relevance

We have discovered that mammalian cells deliberately reprogram the genetic code with the amino acid methionine upon innate immune activation and oxidative stress. Here we aim to establish biology of mis-translation via tRNA misacylation as a new mechanism of stress response in mammalian cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-NDPA-A (01))
Program Officer
Bender, Michael T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Medicine
United States
Zip Code
Clark, Wesley C; Evans, Molly E; Dominissini, Dan et al. (2016) tRNA base methylation identification and quantification via high-throughput sequencing. RNA 22:1771-1784
Saikia, Mridusmita; Wang, Xiaoyun; Mao, Yuanhui et al. (2016) Codon optimality controls differential mRNA translation during amino acid starvation. RNA 22:1719-1727
Zhou, Katherine I; Parisien, Marc; Dai, Qing et al. (2016) N(6)-Methyladenosine Modification in a Long Noncoding RNA Hairpin Predisposes Its Conformation to Protein Binding. J Mol Biol 428:822-33
Schwartz, Michael H; Pan, Tao (2016) Determining the fidelity of tRNA aminoacylation via microarrays. Methods :
Wang, Xiaoyun; Chow, Christina R; Ebine, Kazumi et al. (2016) Interaction of tRNA with MEK2 in pancreatic cancer cells. Sci Rep 6:28260
Zheng, Guanqun; Qin, Yidan; Clark, Wesley C et al. (2015) Efficient and quantitative high-throughput tRNA sequencing. Nat Methods 12:835-7
Pan, Tao (2013) Adaptive translation as a mechanism of stress response and adaptation. Annu Rev Genet 47:121-37
Parisien, Marc; Wang, Xiaoyun; Pan, Tao (2013) Diversity of human tRNA genes from the 1000-genomes project. RNA Biol 10:1853-67
Wiltrout, Elizabeth; Goodenbour, Jeffrey M; Fréchin, Mathieu et al. (2012) Misacylation of tRNA with methionine in Saccharomyces cerevisiae. Nucleic Acids Res 40:10494-506