The Skaggs Institute
for Chemical Biology
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
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.
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
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.
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.