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

Journal article
Authors Thomas J. Nicholls
C. A. Nadalutti
E. Motori
E. W. Sommerville
G. S. Gorman
Swaraj Basu
Emily Hoberg
D. M. Turnbull
P. F. Chinnery
N. G. Larsson
Erik Larsson
Maria Falkenberg
R. W. Taylor
J. D. Griffith
Claes M Gustafsson
Published in Molecular Cell
Volume 69
Issue 1
Pages 9-23.e6
ISSN 1097-2765
Publication year 2018
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 9-23.e6
Language en
Keywords DNA replication, DNA separation, mitochondrion, nucleoid, progressive external ophthalmoplegia, segregation, topoisomerase, catenane, DNA topoisomerase, mitochondrial DNA, allelism, Article, chronic progressive external ophthalmoplegia, complex formation, controlled study, DNA determination, DNA structure, gene deletion, genetic variation, human, human cell, protein function
Subject categories Medical cell biology, Cell Biology


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. © 2017 Elsevier Inc.

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