title: Adaptation of topoisomerase I paralogs to nuclear and mitochondrial DNA.
abstract: 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.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich-Heine-University, Medical School, D-40225 Düsseldorf, Germany.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dalla Rosa
authors.forename: Steffi
authors.initials: S
authors.lastname: Goffart
authors.forename: Melanie
authors.initials: M
authors.lastname: Wurm
authors.forename: Constanze
authors.initials: C
authors.lastname: Wiek
authors.forename: Frank
authors.initials: F
authors.lastname: Essmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Sobek
authors.forename: Peter
authors.initials: P
authors.lastname: Schroeder
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zhang
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Christian
authors.initials: C
authors.lastname: Mielke
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Fritz
authors.initials: F
authors.lastname: Boege
authors.forename: Morten O
authors.initials: MO
authors.lastname: Christensen
mesh_terms: D000222:Adaptation, Physiological; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D002875:Chromosomes / Q000201:enzymology; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D020440:Gene Duplication; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D010641:Phenotype; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic
chemical_list: D004272:DNA, Mitochondrial; D004247:DNA; D004264:DNA Topoisomerases, Type I