title: A pathogenesis-associated mutation in human mitochondrial tRNALeu(UUR) leads to reduced 3'-end processing and CCA addition.
abstract: 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. tRNALeu(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.
authors.affiliation: York College/CUNY, Jamaica, NY 11451, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Levinger
authors.forename: Isabel
authors.initials: I
authors.lastname: Oestreich
authors.forename: Catherine
authors.initials: C
authors.lastname: Florentz
authors.forename: Mario
authors.initials: M
authors.lastname: Mörl
mesh_terms: D006801:Humans; D007700:Kinetics; D028361:Mitochondrial Diseases / Q000235:genetics*; D009690:Nucleic Acid Conformation; D017354:Point Mutation; D012313:RNA / Q000235:genetics* / Q000502:physiology; D026721:RNA 3' End Processing; D012316:RNA Nucleotidyltransferases / Q000378:metabolism; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu / Q000235:genetics* / Q000502:physiology
chemical_list: D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu; D012313:RNA; D012316:RNA Nucleotidyltransferases; C023198:tRNA nucleotidyltransferase