The exonuclease activity of DNA polymerase γ is required for ligation during mitochondrial DNA replication

Bertil Macao, Jay P. Uhler (), Triinu Siibak, Xuefeng Zhu, Yonghong Shi, Wenwen Sheng, Monica Olsson, James B. Stewart, Claes M. Gustafsson and Maria Falkenberg ()
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Bertil Macao: University of Gothenburg
Jay P. Uhler: University of Gothenburg
Triinu Siibak: University of Gothenburg
Xuefeng Zhu: University of Gothenburg
Yonghong Shi: University of Gothenburg
Wenwen Sheng: University of Gothenburg
Monica Olsson: University of Gothenburg
James B. Stewart: Max Planck Institute for Biology of Ageing
Claes M. Gustafsson: University of Gothenburg
Maria Falkenberg: University of Gothenburg

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Mitochondrial DNA (mtDNA) polymerase γ (POLγ) harbours a 3′–5′ exonuclease proofreading activity. Here we demonstrate that this activity is required for the creation of ligatable ends during mtDNA replication. Exonuclease-deficient POLγ fails to pause on reaching a downstream 5′-end. Instead, the enzyme continues to polymerize into double-stranded DNA, creating an unligatable 5′-flap. Disease-associated mutations can both increase and decrease exonuclease activity and consequently impair DNA ligation. In mice, inactivation of the exonuclease activity causes an increase in mtDNA mutations and premature ageing phenotypes. These mutator mice also contain high levels of truncated, linear fragments of mtDNA. We demonstrate that the formation of these fragments is due to impaired ligation, causing nicks near the origin of heavy-strand DNA replication. In the subsequent round of replication, the nicks lead to double-strand breaks and linear fragment formation.

Date: 2015
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DOI: 10.1038/ncomms8303

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