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Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions.

ABSTRACT: Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and also accumulate during normal human ageing. The mechanisms underlying mtDNA deletions remain unknown although several models have been proposed. Here we use deep sequencing to characterize abundant mtDNA deletions in patients with mutations in mitochondrial DNA replication factors, and show that these have distinct directionality and repeat characteristics. Furthermore, we recreate the deletion formation process in vitro using only purified mitochondrial proteins and defined DNA templates. Based on our in vivo and in vitro findings, we conclude that mtDNA deletion formation involves copy-choice recombination during replication of the mtDNA light strand.

SUBMITTER: Persson O

PROVIDER: S-EPMC6377680 | biostudies-other | 2019 Feb

REPOSITORIES: biostudies-other

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Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions.

Persson Örjan Ö Muthukumar Yazh Y Basu Swaraj S Jenninger Louise L Uhler Jay P JP Berglund Anna-Karin AK McFarland Robert R Taylor Robert W RW Gustafsson Claes M CM Larsson Erik E Falkenberg Maria M

Nature communications 20190215 1

Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and also accumulate during normal human ageing. The mechanisms underlying mtDNA deletions remain unknown although several models have been proposed. Here we use deep sequencing to characterize abundant mtDNA deletions in patients with mutations in mitochondrial DNA replication factors, and show that these have distinct directionality and repeat characteristics. Furthermore, we recreate the deletion formation process i ...[more]

PMID: 30770810

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Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions

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