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Lookup NU author(s): Dr Jim StewartORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Macao B, Uhler JP, Siibak T, Zhu X, Shi Y, Sheng W, Olsson M, Stewart JB, Gustafsson CM, Falkenberg M
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2015
Volume: 6
Online publication date: 22/06/2015
Acceptance date: 27/04/2015
Date deposited: 21/12/2020
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/ncomms8303
DOI: 10.1038/ncomms8303
PubMed id: 26095671
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