Bratic, A;
Kauppila, TES;
Macao, B;
Grönke, S;
Siibak, T;
Stewart, JB;
Baggio, F;
... Larsson, N-G; + view all
(2015)
Complementation between polymerase- and exonuclease-deficient mitochondrial DNA polymerase mutants in genomically engineered flies.
Nature Communications
, 6
, Article 8808. 10.1038/ncomms9808.
Preview |
Text
Partridge_1475541_ncomms9808.pdf - Published Version Download (1MB) | Preview |
Preview |
Text
Partridge_1475541_supplementary info.pdf - Accepted Version Download (2MB) | Preview |
Abstract
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.
| Type: | Article |
|---|---|
| Title: | Complementation between polymerase- and exonuclease-deficient mitochondrial DNA polymerase mutants in genomically engineered flies |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/ncomms9808 |
| Publisher version: | http://dx.doi.org/10.1038/ncomms9808 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License (CC-BY). The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Biological sciences, biochemistry, molecular biology |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1475541 |
Archive Staff Only
 |
View Item |
