This project is focused on two components of the translation apparatus that are responsible for the rules of the modern, universal genetic code. The code is established by aminoacylation reactions catalyzed by enzymes known as aminoacyl transfer RNA synthetases. In these reactions, each amino acid is matched with its nucleotide triplet imbedded in the anticodon of the cognate transfer RNA. The enzymes are ancient and appeared at or before the split that gave rise to the three kingdoms of living organisms. Highly specific interactions between the synthetases, their tRNAs, and their amino acids are essential for the accuracy of and maintenance of the code. Standard protein-nucleic acid or protein-small molecule interactions are by themselves not able to sustain the code. Instead, editing reactions that are tRNA-dependent are critical for preventing errors of aminoacylation that would invade, or contaminate, the code. In the proposed work, genetic manipulations explore the consequences of disruption of the editing activity of a specific synthetase. This work includes investigations of the production of statistical proteins, where more than one amino acid can be inserted at a specific codon in an mRNA. Also, with the editing center of a synthetase disabled, the compensatory cellular mechanisms that can be recruited to clear errors of aminoacylation will be studied. These investigations will be extended to study the disruption of editing in mammalian cells and the possible connections to disease. Further work focuses on how nature has developed other mechanisms to preserve the integrity of the code, including the complexities found in eukaryotic cells where mitochondrial and cytoplasmic systems of protein synthesis appear to force changes in the rules for synthetase-tRNA recognition. ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Genetics Study Section (GEN)
Program Officer
Bender, Michael T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Chong, Yeeting E; Guo, Min; Yang, Xiang-Lei et al. (2018) Distinct ways of G:U recognition by conserved tRNA binding motifs. Proc Natl Acad Sci U S A 115:7527-7532
Song, Youngzee; Zhou, Huihao; Vo, My-Nuong et al. (2017) Double mimicry evades tRNA synthetase editing by toxic vegetable-sourced non-proteinogenic amino acid. Nat Commun 8:2281
Naganuma, Masahiro; Sekine, Shun-ichi; Chong, Yeeting Esther et al. (2014) The selective tRNA aminoacylation mechanism based on a single G•U pair. Nature 510:507-11
Ofir-Birin, Yifat; Fang, Pengfei; Bennett, Steven P et al. (2013) Structural switch of lysyl-tRNA synthetase between translation and transcription. Mol Cell 49:30-42
Klipcan, Liron; Safro, Mark; Schimmel, Paul (2013) Anticodon G recognition by tRNA synthetases mimics the tRNA core. Trends Biochem Sci 38:229-32
Guo, Min; Schimmel, Paul (2013) Essential nontranslational functions of tRNA synthetases. Nat Chem Biol 9:145-53
Zhou, Huihao; Sun, Litao; Yang, Xiang-Lei et al. (2013) ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase. Nature 494:121-4
Park, Min Chul; Kang, Taehee; Jin, Da et al. (2012) Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis. Proc Natl Acad Sci U S A 109:E640-7
Guo, Min; Schimmel, Paul (2012) Structural analyses clarify the complex control of mistranslation by tRNA synthetases. Curr Opin Struct Biol 22:119-26
Sajish, Mathew; Zhou, Quansheng; Kishi, Shuji et al. (2012) Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-? and p53 signaling. Nat Chem Biol 8:547-54

Showing the most recent 10 out of 130 publications