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Publication

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

Molecular cell | 2018

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.

Pubmed ID: 29290614 RIS Download

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Associated grants

Agency: NCI NIH HHS, United States
Id: P01 CA019014
Agency: Medical Research Council, United Kingdom
Id: MC_UP_1501/2
Agency: Medical Research Council, United Kingdom
Id: MR/K000608/1
Agency: Wellcome Trust, United Kingdom
Id: 101876/Z/13/Z
Agency: Medical Research Council, United Kingdom
Id: MR/L016354/1
Agency: NCI NIH HHS, United States
Id: P30 CA016086
Agency: NIGMS NIH HHS, United States
Id: R01 GM031819
Agency: Medical Research Council, United Kingdom
Id: G0800674
Agency: Wellcome Trust, United Kingdom
Id: 203105/Z/16/Z
Agency: Medical Research Council, United Kingdom
Id: G0601943
Agency: Wellcome Trust, United Kingdom
Agency: NIEHS NIH HHS, United States
Id: R01 ES013773
Agency: Department of Health, United Kingdom

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LAST (tool)

RRID:SCR_006119

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RRID:SCR_013517

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RRID:SCR_014492

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Bowtie 2 (tool)

RRID:SCR_016368

Ultrafast and memory efficient tool for aligning sequencing reads to long reference sequences. Supports gapped, local, and paired end alignment modes. More suited to finding longer, gapped alignments in comparison with original Bowtie method.

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