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Nucleic Acids Research, 2003, Vol. 31, No. 7 1904-1912
© 2003 Oxford University Press

Pathology-related substitutions in human mitochondrial tRNAIle reduce precursor 3' end processing efficiency in vitro

Louis Levinger1,2, Richard Giegé1 and Catherine Florentz1

1 UPR 9002 de CNRS, IBMC 15 rue René Descartes, 67084 Strasbourg Cedex, France and 2 York College/CUNY, 94-20 Guy R. Brewer Boulevard, Jamaica, NY 11451, USA

*To whom correspondence should be addressed at York College/CUNY, 94-20 Guy R. Brewer Boulevard, Jamaica, NY 11451, USA. Tel: +1 718 262 2704; Fax: +1 718 262 2652; Email: louie{at}york.cuny.edu

The human mitochondrial genome encodes 22 tRNAs interspersed among the two rRNAs and 11 mRNAs, often without spacers, suggesting that tRNAs must be efficiently excised. Numerous maternally transmitted diseases and syndromes arise from mutations in mitochondrial tRNAs, likely due to defect(s) in tRNA metabolism. We have systematically explored the effect of pathogenic mutations on tRNAIle precursor 3' end maturation in vitro by 3'-tRNase. Strikingly, four pathogenic tRNAIle mutations reduce 3'-tRNase processing efficiency (Vmax / KM) to ~10-fold below that of wild-type, principally due to lower Vmax. The structural impact of mutations was sought by secondary structure probing and wild-type tRNAIle precursor was found to fold into a canonical cloverleaf. Among the mutant tRNAIle precursors with the greatest 3' end processing deficiencies, only G4309A displays a secondary structure substantially different from wild-type, with changes in the T domain proximal to the substitution. Reduced efficiency of tRNAIle precursor 3' end processing, in one case associated with structural perturbations, could thus contribute to human mitochondrial diseases caused by mutant tRNAs.


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