Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA.
Mol Cell
; 69(1): 9-23.e6, 2018 01 04.
Article
em En
| MEDLINE
| ID: mdl-29290614
ABSTRACT
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.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
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DNA Topoisomerases Tipo I
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Segregação de Cromossomos
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Replicação do DNA
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Dinâmica Mitocondrial
Limite:
Humans
Idioma:
En
Revista:
Mol Cell
Ano de publicação:
2018
Tipo de documento:
Article