Nucleic Acids Research Advance Access originally published online on August 31, 2009
Nucleic Acids Research 2009 37(19):6414-6428; doi:10.1093/nar/gkp708
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Nucleic Acids Research, 2009, Vol. 37, No. 19 6414-6428
© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Genome Integrity, Repair and Replication |
Adaptation of topoisomerase I paralogs to nuclear and mitochondrial DNA
1Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich-Heine-University, Medical School, D-40225 Düsseldorf, Germany, 2Institute of Medical Technology, Tampere, Finland, 3Department of Pediatric Oncology, Hematology and Immunology, Children’s Hospital, Heinrich-Heine-University, Medical School, D-40225 Düsseldorf, 4Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, 5Environmental Health Research Institute at the Heinrich-Heine-University, D-40225 Düsseldorf, Germany and 6Laboratory of Molecular Pharmacology, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA
*To whom correspondence should be addressed. Tel: +49 211 811 8013; Fax: +49 211 8118021; Email: christensen{at}med.uni-duesseldorf.de
Correspondence may also be addressed to Fritz Boege. Tel: +49 211 811 7769; Fax: +49 211 811 8021; Email: boege{at}med.uni-duesseldorf.de
Received May 25, 2009. Accepted August 9, 2009.
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.