Chomyn, A. and Martinuzzi, A. and Yoneda, M. and Daga, A. and Hurko, O. and Johns, D. and Lai, S. T. and Nonaka, I. and Angelini, C. and Attardi, G. (1992) MELAS Mutation in mtDNA Binding Site for Transcription Termination Factor Causes Defects in Protein Synthesis and in Respiration but no Change in Levels of Upstream and Downstream Mature Transcripts. Proceedings of the National Academy of Sciences of the United States of America, 89 (10). pp. 4221-4225. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:20120309-160913724
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The pathogenetic mechanism of the mitochondrial tRNA^(Leu)_(UUR) gene mutation responsible for the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome was investigated in transformants obtained by transfer of mitochondria from three genetically unrelated MELAS patients into human mitochondrial DNA (mtDNA)-less (ρ°) cells. Marked defects in mitochondrial protein synthesis and respiratory activity were observed in transformants containing virtually pure mutant mtDNA, as compared to the parent of the ρ° cells (the 143B cell line) or to transformants containing exclusively wild-type mtDNA, derived from one of the patients or a maternally related asymptomatic individual. A striking protective effect against the mutation was exerted in the transformants by levels of residual wild-type mtDNA above 6%. The MELAS mutation occurs within the mtDNA binding site for a protein factor (mTERF) that promotes termination of transcription at the 16S rRNA/tRNA^(Leu)_(UUR) gene boundary. A marked decrease in affinity of purified mTERF for the mutant target sequence was observed in in vitro assays. By contrast, RNA transfer hybridization experiments failed to show any significant change in the steady-state amounts of the two rRNA species, encoded upstream of the termination site, and of the mRNAs encoded downstream, in the transformants carrying the MELAS mutation.
|Additional Information:||© 1992 National Academy of Sciences. Contributed by G. Attardi, January 13, 1992. We are very grateful to Dr. M. King for isolating the 2S-derived mitochondrial transformants. We thank Drs. S. Horai and C. Rossi for providing the clones MTC2 and A2, respectively. The technical assistance of Ms. B. Keeley, A. Drew, and L. Tefo is gratefully acknowledged. These investigations were supported by Grant GM11726 from the National Institutes of Health to G.A., Muscular Dystrophy Association Grant 37826 to G.A. and A.C., a fellowship from the Associazione per la Promozione delle Richerche Neurologiche to A.M., and a Gosney Fellowship to M.Y. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.|
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|Deposited By:||Jason Perez|
|Deposited On:||13 Mar 2012 15:56|
|Last Modified:||13 Mar 2012 15:56|
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