Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 337, Issue 3, Pages 535-544Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2004.02.008
Keywords
mitochondrial diseases; 3 '-end processing; CCA addition; tRNA nucleotidyltransferase; 3 '-tRNase
Categories
Funding
- NIGMS NIH HHS [T34GM08498, F33-GM64266, S06GM08153] Funding Source: Medline
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Point mutations in mitochondrial tRNAs can cause severe multisystemic disorders such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and myoclonus epilepsy with ragged-red fibers (MERRF). Some of these mutations impair one or more steps of tRNA maturation and protein biosynthesis including 5-end-processing, post-transcriptional base modification, structural stability aminoacylation, and formation of tRNA-ribosomal complexes. tRNA Leu(UUR), an etiologic hot spot for such diseases, harbors 20 of more than 90 disease-associated mutations described to date. Here, the pathogenesis-associated base substitutions A3243G, T3250C, T3271C, A3302G and C3303T within this tRNA were tested for their effects on endonucleolytic 3'-end processing and CCA addition at the tRNA 3'-terminus. Whereas mutations A3243G, A3302G and C3303T reduced the efficiency of 3'-end cleavage, only the C3303T substitution was a less efficient substrate for CCA addition. These results support the view that pathogenesis may be elicited through cumulative effects of tRNA mutations: a mutation can impede several pre-tRNA processing steps, with each such reduction contributing to the overall impairment of tRNA function. (C) 2004 Elsevier Ltd. All rights reserved.
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