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Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing

DNA damage has been implicated in ageing, but direct evidence for a causal relationship is lacking, owing to the difficulty of inducing defined DNA lesions in cells and tissues without simultaneously damaging other biomolecules and cellular structures. Here we directly test whether highly toxic DNA...

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Autores principales: White, Ryan R., Milholland, Brandon, de Bruin, Alain, Curran, Samuel, Laberge, Remi-Martin, van Steeg, Harry, Campisi, Judith, Maslov, Alexander Y., Vijg, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394211/
https://www.ncbi.nlm.nih.gov/pubmed/25858675
http://dx.doi.org/10.1038/ncomms7790
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author White, Ryan R.
Milholland, Brandon
de Bruin, Alain
Curran, Samuel
Laberge, Remi-Martin
van Steeg, Harry
Campisi, Judith
Maslov, Alexander Y.
Vijg, Jan
author_facet White, Ryan R.
Milholland, Brandon
de Bruin, Alain
Curran, Samuel
Laberge, Remi-Martin
van Steeg, Harry
Campisi, Judith
Maslov, Alexander Y.
Vijg, Jan
author_sort White, Ryan R.
collection PubMed
description DNA damage has been implicated in ageing, but direct evidence for a causal relationship is lacking, owing to the difficulty of inducing defined DNA lesions in cells and tissues without simultaneously damaging other biomolecules and cellular structures. Here we directly test whether highly toxic DNA double-strand breaks (DSBs) alone can drive an ageing phenotype using an adenovirus-based system based on tetracycline-controlled expression of the SacI restriction enzyme. We deliver the adenovirus to mice and compare molecular and cellular end points in the liver with normally aged animals. Treated, 3-month-old mice display many, but not all signs of normal liver ageing as early as 1 month after treatment, including ageing pathologies, markers of senescence, fused mitochondria and alterations in gene expression profiles. These results, showing that DSBs alone can cause distinct ageing phenotypes in mouse liver, provide new insights in the role of DNA damage as a driver of tissue ageing.
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spelling pubmed-43942112015-09-01 Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing White, Ryan R. Milholland, Brandon de Bruin, Alain Curran, Samuel Laberge, Remi-Martin van Steeg, Harry Campisi, Judith Maslov, Alexander Y. Vijg, Jan Nat Commun Article DNA damage has been implicated in ageing, but direct evidence for a causal relationship is lacking, owing to the difficulty of inducing defined DNA lesions in cells and tissues without simultaneously damaging other biomolecules and cellular structures. Here we directly test whether highly toxic DNA double-strand breaks (DSBs) alone can drive an ageing phenotype using an adenovirus-based system based on tetracycline-controlled expression of the SacI restriction enzyme. We deliver the adenovirus to mice and compare molecular and cellular end points in the liver with normally aged animals. Treated, 3-month-old mice display many, but not all signs of normal liver ageing as early as 1 month after treatment, including ageing pathologies, markers of senescence, fused mitochondria and alterations in gene expression profiles. These results, showing that DSBs alone can cause distinct ageing phenotypes in mouse liver, provide new insights in the role of DNA damage as a driver of tissue ageing. Nature Pub. Group 2015-04-10 /pmc/articles/PMC4394211/ /pubmed/25858675 http://dx.doi.org/10.1038/ncomms7790 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. 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/
spellingShingle Article
White, Ryan R.
Milholland, Brandon
de Bruin, Alain
Curran, Samuel
Laberge, Remi-Martin
van Steeg, Harry
Campisi, Judith
Maslov, Alexander Y.
Vijg, Jan
Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing
title Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing
title_full Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing
title_fullStr Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing
title_full_unstemmed Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing
title_short Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing
title_sort controlled induction of dna double-strand breaks in the mouse liver induces features of tissue ageing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394211/
https://www.ncbi.nlm.nih.gov/pubmed/25858675
http://dx.doi.org/10.1038/ncomms7790
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