Mitochondrial topoisomerases and alternative splicing of the human TOP1mt gene.
ABSTRACT Mitochondria are the only organelles containing metabolically active DNA besides nuclei. By analogy with the nuclear topoisomerases, mitochondrial topoisomerase activities are probably critical for maintaining the topology of mitochondrial DNA during replication, transcription, and repair. Mitochondrial diseases include a wide range of defects including neurodegeneracies, myopathies, metabolic abnormalities and premature aging. Vertebrates only have one known specific mitochondrial topoisomerase gene (TOP1mt), coding for a type IB topoisomerase. Like the mitochondrial DNA and RNA polymerase, the TOP1mt gene is encoded in the nuclear genome. The TOP1mt gene possesses the 13 exon Top1B signature motif and codes for a mitochondrial targeting signals at the N-terminus of the Top1mt polypeptide. This review summarizes our current knowledge of mitochondrial topoisomerases (type IA, IB and type II) in eukaryotes including budding and fission yeasts (Saccharomyces cerevisiae and Schizosaccharomyces pombe) and protozoan parasites (kinetoplastidiae and plasmodium). It also includes new data showing alternative splice variants of human TOP1mt.
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Article: Human mitochondrial topoisomerase I.[show abstract] [hide abstract]
ABSTRACT: Tension generated in the circular mitochondrial genome during replication and transcription points to the need for mtDNA topoisomerase activity. Here we report a 601-aa polypeptide highly homologous to nuclear topoisomerase I. The N-terminal domain of this novel topoisomerase contains a mitochondrial localization sequence and lacks a nuclear localization signal. Therefore, we refer to this polypeptide as top1mt. The pattern of top1mt expression matches the requirement for high mitochondrial activity in specific tissues. top1mt is a type IB topoisomerase that requires divalent metal (Ca(2+) or Mg(2+)) and alkaline pH for optimum activity. The TOP1mt gene is highly homologous to the nuclear TOP1 gene and consists of 14 exons. It is localized on human chromosome 8q24.3.Proceedings of the National Academy of Sciences 10/2001; 98(19):10608-13. · 9.74 Impact Factor
Article: Mitochondrial disease.[show abstract] [hide abstract]
ABSTRACT: Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. This review updates the topic of mitochondrial diseases by reviewing the most important recent advances in this area. The factors influencing inheritance, maintenance and replication of mtDNA are reviewed and the genotype-phenotype of mtDNA disorders has been expanded, with new insights into epidemiology, pathogenesis and its role in ageing. Recently identified nuclear gene mutations of mitochondrial proteins include mutations of frataxin causing Friedreich's ataxia, PINK1, DJ1 causing Parkinson's disease and POLG causing infantile mtDNA depletion syndrome, ophthalmoplegia, parkinsonism, male subfertility and, in a transgenic mouse model, premature senescence. Mitochondrial defects in neurodegenerative diseases include Parkinson's, Alzheimer's and Huntington's disease. Improved understanding of mtDNA inheritance and mutation penetrance patterns, and novel techniques for mtDNA modification offer significant prospects for more accurate genetic counselling and effective future therapies.The Lancet 08/2006; 368(9529):70-82. · 39.06 Impact Factor
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ABSTRACT: DNA topoisomerase II (topo II), an enzyme essential for cellular replication, is an eminent target for antimicrobial therapy against Leishmania chagasi, the major cause of visceral leishmaniasis in Latin America. The complete L. chagasi (Lch) TOP2 gene, encoding L. chagasi topo II, was isolated from genomic DNA using the polymerase chain reaction. The LchTOP2 gene revealed an open reading frame (ORF) of 3,711 base pairs predicting a protein with 1,236 amino acids and an estimated molecular weight of 140 kDA. The L. chagasi topo II sequence had high identity with the L. donovani topo II (98.8%) and L. infantum topo II (98.7%), followed by Crithidia fasciculata topo II (84.4%), Trypanosoma cruzi topo II (67.6%) and Trypanosoma brucei topo II (66.6%). Lch topo II had low identity with the human homologs htopo II alpha (26.3%) and htopo II beta (26.4%). Differences between L. chagasi TOP2 and human TOP2 genes suggest that leishmanial topo II is a potential target for the development of new antileishmanial agents.Scandinavian Journal of Infectious Diseases 02/2003; 35(11-12):826-9. · 1.71 Impact Factor