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Human mitochondrial topoisomerase I.

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.

SUBMITTER: Zhang H

PROVIDER: S-EPMC58513 | biostudies-literature | 2001 Sep

REPOSITORIES: biostudies-literature

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Human mitochondrial topoisomerase I.

Zhang H H Barceló J M JM Lee B B Kohlhagen G G Zimonjic D B DB Popescu N C NC Pommier Y Y

Proceedings of the National Academy of Sciences of the United States of America 20010828 19

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 acti ...[more]

PMID: 11526219

Similar Datasets

Mapping topoisomerase sites in mitochondrial DNA with a poisonous mitochondrial topoisomerase I (Top1mt).

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| S-EPMC4140277 | biostudies-literature

The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.

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| S-EPMC6325124 | biostudies-literature

Negative regulation of mitochondrial transcription by mitochondrial topoisomerase I.

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Mitochondrial topoisomerase I is critical for mitochondrial integrity and cellular energy metabolism.

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| S-EPMC3401127 | biostudies-literature

Coordinated regulation of mitochondrial topoisomerase IB with mitochondrial nuclear encoded genes and MYC.

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| S-EPMC3159436 | biostudies-literature

Top3α is the replicative topoisomerase in mitochondrial DNA replication.

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| S-EPMC9410902 | biostudies-literature

Adaptation of topoisomerase I paralogs to nuclear and mitochondrial DNA.

Project description:Topoisomerase I is essential for DNA metabolism in nuclei and mitochondria. In yeast, a single topoisomerase I gene provides for both organelles. In vertebrates, topoisomerase I is divided into nuclear and mitochondrial paralogs (Top1 and Top1mt). To assess the meaning of this gene duplication, we targeted Top1 to mitochondria or Top1mt to nuclei. Overexpression in the fitting organelle served as control. Targeting of Top1 to mitochondria blocked transcription and depleted mitochondrial DNA. This was also seen with catalytically inactive Top1 mutants, but not with Top1mt overexpressed in mitochondria. Targeting of Top1mt to the nucleus revealed that it was much less able to interact with mitotic chromosomes than Top1 overexpressed in the nucleus. Similar experiments with Top1/Top1mt hybrids assigned these functional differences to structural divergences in the DNA-binding core domains. We propose that adaptation of this domain to different chromatin environments in nuclei and mitochondria has driven evolutional development and conservation of organelle-restricted topoisomerase I paralogs in vertebrates.

| S-EPMC2770673 | biostudies-literature

Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2.

Project description:Maintenance of topological homeostasis is vital for gene expression and genome replication in all organisms. Similar to other circular genomes, also mitochondrial DNA (mtDNA) is known to exist in various different topological forms, although their functional significance remains unknown. We report here that both known type II topoisomerases Top2α and Top2β are present in mammalian mitochondria, with especially Top2β regulating the supercoiling state of mtDNA. Loss of Top2β or its inhibition by ciprofloxacin results in accumulation of positively supercoiled mtDNA, followed by cessation of mitochondrial transcription and replication initiation, causing depletion of mtDNA copy number. These mitochondrial effects block both cell proliferation and differentiation, possibly explaining some of the side effects associated with fluoroquinolone antibiotics. Our results show for the first time the importance of topology for maintenance of mtDNA homeostasis and provide novel insight into the mitochondrial effects of fluoroquinolones.

| S-EPMC6182158 | biostudies-literature

Coordinating the two protomer active sites of human topoisomerase IIalpha: nicks as topoisomerase II poisons.

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| S-EPMC2716134 | biostudies-literature

Drosophila mitochondrial topoisomerase III alpha affects the aging process via maintenance of mitochondrial function and genome integrity.

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| S-EPMC4828762 | biostudies-literature

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