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The Skaggs Institute
for Chemical Biology


Scientific Report 2008




Role of Mistranslation in Disease

P. Schimmel, X.-L. Yang, R. Belani, Y. Chong, Z. Druzina, J. Frater, M. Guo, R.-T. Guo, M. Hanan, W. He, I.L. Jung, M. Kapoor, S.H. Lee, J. Liu, E. Merriman, M.H. Nawaz, R. Shapiro, Y.Z. Song, M.-N. Vo, W. Zhang, Q. Zhou

Mistranslation occurs when the wrong amino acid is inserted into a growing polypeptide chain during protein synthesis. Most usually, proteins are error-free; that is, each specific protein has its own, specific amino acid sequence that is defined by the gene that encodes the protein. (The process of protein synthesis "translates" the sequence of a gene into the corresponding protein sequence.) When an error is made, so that the wrong amino acid occasionally appears at a specific location in the sequence of a protein, this aberration can lead to a protein with altered biological activity. Additionally or alternatively, the error-containing protein may misfold. Recently, we showed that mistranslation that causes altered protein structure and function is connected to disease.

Normally, errors of translation are prevented by the editing activities of tRNA synthetases. These synthetases attach amino acids to tRNAs, matching each amino acid to its cognate tRNA partner. The attached amino acid is then carried to the ribosome, where it is inserted into a growing polypeptide chain at the position specified by the anticodon of the tRNA. If the wrong amino acid is accidentally attached to a particular tRNA and is not corrected by the editing activity of the appropriate tRNA synthetase, then that amino acid is carried in the same way to the ribosome and inserted into a growing polypeptide. This insertion is at the place normally occupied by the correct amino acid.

Mutations in the editing centers of tRNA synthetases can thus lead to mistranslation. Recently, we showed that mistranslation arising from such mutations is deleterious to bacterial and mammalian cells. In addition, we found that a mild editing defect in a specific tRNA synthetase (alanyl-tRNA synthetase) led to neurodegeneration in mice.

Currently, we are focusing on the possibility that editing defects are causally connected to the etiology of some cancers. Because cancer is mostly a disease of aging, the random occurrence of mutations in the editing domains of tRNA synthetases in somatic cells can lead to mistranslation in those tissues. In other studies, we established that in aging bacteria, an editing-defective tRNA synthetase (the defect itself caused by a mutation in its editing domain) can lead to mutations in the error-prone DNA repair apparatus. When error-prone repair is perturbed, random errors spontaneously occur more frequently in the genome. We envision that a similar situation happens in mammalian cells; that is, an editing-defective tRNA synthetase can itself induce more mutational errors in the genome as the organism ages. Some of these mutations might occur in oncogenes that when activated lead to transformation to the oncogenic state.

With this possibility in mind, we established a collaboration with P. Vogt, Scripps Research, to see whether, in a model system developed in Dr. Vogt's laboratory, oncogenesis can be induced by an editing-defective tRNA synthetase. At the same time, we are investigating activities of enzymes associated with DNA repair to see if in mammalian cells carrying an editing defect, one or more of these enzymes is affected by mistranslation. A perturbation of one of the enzymes associated with DNA repair could lead to the fixing of random mutations into the genome. Some of these mutations might occur in oncogenes.

Publications

Beebe, K., Mock, M., Merriman, E., Schimmel, P. Distinct domains of tRNA synthetase recognize the same base pair. Nature 451:90, 2008.

Cheng, G., Zhang, H., Yang, X.-L., Tzima, E., Ewalt, K.L., Schimmel, P., Faber, J.E. Effect of mini-tyrosyl-tRNA synthetase on ischemic angiogenesis, leukocyte recruitment, and vascular permeability. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295:R1138, 2008.

Chong, Y.-E., Yang, X.-L., Schimmel, P. Natural homology of tRNA synthetase editing domain rescues conditional lethality caused by mistranslation. J. Biol. Chem. 283:30073, 2008.

Greenberg, Y., King, M., Kiosses, W.B., Ewalt, K., Yang, X.-L., Schimmel, P., Reader, J. S., Tzima, E. The novel fragment of tyrosyl-tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells. FASEB J. 22:1597, 2008.

Guo, M., Ignatov, M., Musier-Forsyth, K., Schimmel, P., Yang, X.-L. Crystal structure of novel tetrameric form of human lysyl-tRNA synthetase: implications for multisynthetase complex formation. Proc. Natl. Acad. Sci. U. S. A. 105:2331, 2008.

Kapoor, M., Zhou, Q., Otero, F., Myers, C.A., Bates, A., Belani, R., Liu, J., Luo, J.-K., Tzima, E., Zhang, D.-E., Yang, X.-L., Schimmel, P. Evidence for annexin II-S100A10 complex and plasmin in mobilization of cytokine activity of human TrpRS. J. Biol. Chem. 283:2070. 2008.

Park, S.G., Schimmel, P., Kim, S. Aminoacyl tRNA synthetases and their connections to disease. Proc. Natl. Acad. Sci. U. S. A. 105:11043. 2008.

Schimmel, P. Development of tRNA synthetases and connection to genetic code and disease. Protein Sci. 17:1643, 2008.

Schimmel, P. An editing activity that prevents mistranslation and connection to disease. J. Biol. Chem. 283:28777, 2008.

Zhou, Q., Kiosses, W.B., Liu, J., Schimmel, P. Tumor endothelial cell tube formation model for determining anti-angiogenic activity of a tRNA synthetase cytokine. Methods 44:190, 2008.

 

Paul R. Schimmel, Ph.D.
Ernest and Jean Hahn Professor and Chair of Molecular Biology and Chemistry

Schimmel Web Site