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

Örjan Persson, Yazh Muthukumar, Swaraj Basu, Louise Jenninger, Jay P. Uhler, Anna-Karin Berglund, Robert McFarland, Robert W. Taylor, Claes M. Gustafsson, Erik Larsson () and Maria Falkenberg ()
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Örjan Persson: University of Gothenburg, P.O. Box 440
Yazh Muthukumar: University of Gothenburg, P.O. Box 440
Swaraj Basu: University of Gothenburg, P.O. Box 440
Louise Jenninger: University of Gothenburg, P.O. Box 440
Jay P. Uhler: University of Gothenburg, P.O. Box 440
Anna-Karin Berglund: University of Gothenburg, P.O. Box 440
Robert McFarland: Newcastle University
Robert W. Taylor: Newcastle University
Claes M. Gustafsson: University of Gothenburg, P.O. Box 440
Erik Larsson: University of Gothenburg, P.O. Box 440
Maria Falkenberg: University of Gothenburg, P.O. Box 440

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08673-5

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