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Lookup NU author(s): Dr Thomas Nicholls,
Dr Ewen Sommerville,
Professor Grainne Gorman,
Emeritus Professor Doug Turnbull,
Professor Patrick Chinnery,
Professor Robert Taylor
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Cell Press, 2018.
For re-use rights please refer to the publisher's terms and conditions.
© 2017 Elsevier Inc. 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. Nicholls et al. identify a role for topoisomerase 3α in the separation of mtDNA following replication. Loss of Top3α activity impairs mtDNA segregation and, consequently, segregation of the mtDNA nucleoid within the mitochondrial network. Mutations in TOP3A cause human mitochondrial disease associated with mtDNA deletions and impaired mtDNA separation.
Author(s): Nicholls TJ, Nadalutti CA, Motori E, Sommerville EW, Gorman GS, Basu S, Hoberg E, Turnbull DM, Chinnery PF, Larsson N-G, Larsson E, Falkenberg M, Taylor RW, Griffith JD, Gustafsson CM
Publication type: Article
Publication status: Published
Journal: Molecular Cell
Print publication date: 04/01/2018
Online publication date: 28/12/2017
Acceptance date: 26/11/2017
Date deposited: 05/09/2019
ISSN (print): 1097-2765
ISSN (electronic): 1097-4164
Publisher: Cell Press
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