Browse by author
Lookup NU author(s): Dr Jim StewartORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Replication errors are the main cause of mitochondrial DNA (mtDNA) mutations and a compelling approach to decrease mutation levels would therefore be to increase the fidelity of the catalytic subunit (POLγA) of the mtDNA polymerase. Here we genomically engineer the tamas locus, encoding fly POLγA, and introduce alleles expressing exonuclease- (exo−) and polymerase-deficient (pol−) POLγA versions. The exo− mutant leads to accumulation of point mutations and linear deletions of mtDNA, whereas pol− mutants cause mtDNA depletion. The mutant tamas alleles are developmentally lethal but can complement each other in trans resulting in viable flies with clonally expanded mtDNA mutations. Reconstitution of human mtDNA replication in vitro confirms that replication is a highly dynamic process where POLγA goes on and off the template to allow complementation during proofreading and elongation. The created fly models are valuable tools to study germ line transmission of mtDNA and the pathophysiology of POLγA mutation disease.
Author(s): Bratic A, Kauppila TES, Macao B, Grönke S, Siibak T, Stewart JB, Baggio F, Dols J, Partridge L, Falkenberg M, Wredenberg A, Larsson NG
Publication type: Article
Publication status: Published
Journal: Nature Communications
Online publication date: 10/11/2015
Acceptance date: 06/10/2015
Date deposited: 21/12/2020
ISSN (electronic): 2041-1723
Publisher: Nature Research
PubMed id: 26554610
Altmetrics provided by Altmetric