Wobble modification defect in tRNA disturbs codon-anticodon interaction in a mitochondrial disease

概要

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We previously showed that in mitochondrial tRNA^<Lys> with an A8344G mutation responsible for myoclonus epilepsy associated with ragged-red fibers (MERRF), a subgroup of mitochondrial encephalomyopathic diseases, the normally modified wobble base (a 2-thio-uridine derivative) remains unmodified. Since wobble base modifications are essential for translational efficiency and accuracy, we used mitochondrial components to estimate the translational activity in vitro of purified tRNA^<Lys> carrying the mutation and found no mistranslation of non-cognate codons by the mutant tRNA, but almost complete loss of translational activity for cognate codons. This defective translation was not explained by a decline in amino-acylation or lowered affinity toward elongation factor Tu. However, when direct interaction of the codon with the mutant tRNA^<Lys> defective anticodon was examined by ribosomal binding analysis, the wild-type but not the mutant tRNA^<Lys> bound to an mRNA-ribosome complex. We therefore concluded that the anticodon base modification defect, which is forced by the pathogenic point mutation, disturbs codon-anticodon pairing in the mutant tRNA^<Lys>, leading to a severe reduction in mitochondrial translation that eventually could result in the onset of MERRF.
日本医科大学の論文
2002-03-25