Journal
MOLECULAR CELL
Volume 69, Issue 1, Pages 9-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2017.11.033
Keywords
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Categories
Funding
- Swedish Research Council
- Swedish Cancer Foundation
- European Research Council [683191]
- IngaBritt and Arne Lundberg Foundation
- Knut and Alice Wallenbergs Foundation
- NIH [GM31819, ESO13773]
- Wellcome Centre for Mitochondrial Research [203105/Z/16/Z]
- Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease
- Mitochondrial Disease Patient Cohort (UK) [G0800674]
- UK NIHR Biomedical Research Centre for Ageing and Age-related disease award
- MRC/EPSRC Molecular Pathology Node
- UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children
- Medical Research Council PhD studentship
- Wellcome Trust [101876/Z/13/Z]
- Medical Research Council Mitochondrial Biology Unit [MC_UP_1501/2]
- Medical Research Council (UK) Centre for Translational Muscle Disease research [G0601943]
- EU FP7 TIRCON
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust
- University of Cambridge
- Medical Research Council [MR/K000608/1, MC_UP_1501/2, G0800674, MR/L016354/1, 1594369] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0514-10016, NF-SI-0514-10077] Funding Source: researchfish
- NIHR Newcastle Biomedical Research Centre [BH111030] Funding Source: researchfish
- Wellcome Trust [101876/B/13/Z] Funding Source: researchfish
- MRC [G0601943, G0800674, MR/K000608/1, MR/L016354/1] Funding Source: UKRI
- European Research Council (ERC) [683191] Funding Source: European Research Council (ERC)
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How mtDNA replication is terminated and the newly formed genomes are separated remain unknown. We here demonstrate that the mitochondrial isoform of topoisomerase 3 alpha (Top3 alpha) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLMTop-3 alpha-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 Top3 alpha 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 Top3 alpha as an essential component of the mtDNA replication machinery and as the first component of the mtDNA separation machinery.
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