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J. Biol. Chem., Vol. 277, Issue 25, 22240-22250, June 21, 2002

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The 7472insC Mitochondrial DNA Mutation Impairs the Synthesis and Extent of Aminoacylation of tRNA^Ser(UCN) but Not Its Structure or Rate of Turnover^*

Marina Toompuu^§¶, Takehiro Yasukawa, Tsutomu Suzuki^**, Terhi Hakkinen, Johannes N. Spelbrink, Kimitsuna Watanabe^**, and Howard T. Jacobs^§§

From the  Institute of Medical Technology and Tampere University Hospital, FIN-33014 University of Tampere, Finland, the ^§ National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia, the  Department of Chemistry and Biotechnology, Graduate School of Engineering and the ^** Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo 113-8656, Japan, and the  Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom

The 7472insC mitochondrial DNA mutation in the tRNA^Ser(UCN) gene is associated with sensorineural deafness combined, in some patients, with a wider neurological syndrome. In cultured cybrid cells it causes a 70% decrease in tRNA^Ser(UCN) abundance and mild respiratory impairment, previously suggested to be due to decreased tRNA stability. When mitochondrial transcription was blocked by ethidium bromide treatment, the half-life of the mutant tRNA was not significantly different from that of wild-type tRNA^Ser(UCN). Over-expression of mitochondrial translational elongation factor EF-Tu also had no effect on the mutant phenotype. However, during recovery from prolonged ethidium bromide treatment, the synthesis of the mutant tRNA^Ser(UCN) was specifically impaired, without polarity effects on downstream tRNAs of the light strand transcription unit. We infer that the mutation acts posttranscriptionally to decrease tRNA^Ser(UCN) abundance by affecting its synthesis rather than its stability. The extent of aminoacylation of the mutant tRNA was also decreased by ~25%. In contrast, the mutation had no detectable effect on tRNA^Ser(UCN) base modification or structure other than the insertion of an extra guanosine templated by the mutation, which was structurally protected from nuclease digestion like the surrounding nucleotides. These findings indicate a common molecular process underlying sensorineural deafness caused by mitochondrial tRNA^Ser(UCN) mutations.

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