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Mol Cell. 2018 Jan 4;69(1):9-23.e6. doi: 10.1016/j.molcel.2017.11.033. Epub 2017 Dec 28.

Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA.

Author information

1
Department of Medical Biochemistry and Cell Biology, University of Gothenburg, P.O. Box 440, 405 30 Gothenburg, Sweden.
2
Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27514, USA.
3
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
4
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
5
Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0QQ, UK.
6
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
7
Department of Medical Biochemistry and Cell Biology, University of Gothenburg, P.O. Box 440, 405 30 Gothenburg, Sweden. Electronic address: claes.gustafsson@medkem.gu.se.

Abstract

How mtDNA replication is terminated and the newly formed genomes are separated remain unknown. We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex. Our data indicate that mtDNA replication termination occurs via a hemicatenane formed at the origin of H-strand replication and that Top3α is essential for resolving this structure. Decatenation is a prerequisite for separation of the segregating unit of mtDNA, the nucleoid, within the mitochondrial network. The importance of this process is highlighted in a patient with mitochondrial disease caused by biallelic pathogenic variants in TOP3A, characterized by muscle-restricted mtDNA deletions and chronic progressive external ophthalmoplegia (CPEO) plus syndrome. Our work establishes Top3α as an essential component of the mtDNA replication machinery and as the first component of the mtDNA separation machinery.

KEYWORDS:

DNA replication; DNA separation; mitochondrion; nucleoid; progressive external ophthalmoplegia; segregation; topoisomerase

PMID:
29290614
PMCID:
PMC5935120
DOI:
10.1016/j.molcel.2017.11.033
[Indexed for MEDLINE]
Free PMC Article

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