Molecular Cell
Volume 69, Issue 1, 4 January 2018, Pages 9-23.e6
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Article
Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA

https://doi.org/10.1016/j.molcel.2017.11.033Get rights and content
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Highlights

  • Mitochondrial topoisomerase 3α separates mtDNA following replication

  • Mutations in TOP3A are a cause of human mitochondrial disease

  • mtDNA segregation proceeds via a hemicatenane formed at the origin of replication

  • Loss of Top3α impairs segregation of the mitochondrial nucleoid

Summary

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
topoisomerase
mitochondrion
progressive external ophthalmoplegia
DNA separation
nucleoid
segregation

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