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Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs

The DNA repair proteins poly(ADP-ribose) polymerase-1 (PARP-1), Ku86, and catalytic subunit of DNA-PK (DNA-PKcs) have been involved in telomere metabolism. To genetically dissect the impact of these activities on telomere function, as well as organismal cancer and aging, we have generated mice doubl...

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Autores principales: Espejel, Silvia, Klatt, Peter, Murcia, Josiane Ménissier-de, Martín-Caballero, Juan, Flores, Juana M., Taccioli, Guillermo, de Murcia, Gilbert, Blasco, María A.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172587/
https://www.ncbi.nlm.nih.gov/pubmed/15545322
http://dx.doi.org/10.1083/jcb.200407178
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author Espejel, Silvia
Klatt, Peter
Murcia, Josiane Ménissier-de
Martín-Caballero, Juan
Flores, Juana M.
Taccioli, Guillermo
de Murcia, Gilbert
Blasco, María A.
author_facet Espejel, Silvia
Klatt, Peter
Murcia, Josiane Ménissier-de
Martín-Caballero, Juan
Flores, Juana M.
Taccioli, Guillermo
de Murcia, Gilbert
Blasco, María A.
author_sort Espejel, Silvia
collection PubMed
description The DNA repair proteins poly(ADP-ribose) polymerase-1 (PARP-1), Ku86, and catalytic subunit of DNA-PK (DNA-PKcs) have been involved in telomere metabolism. To genetically dissect the impact of these activities on telomere function, as well as organismal cancer and aging, we have generated mice doubly deficient for both telomerase and any of the mentioned DNA repair proteins, PARP-1, Ku86, or DNA-PKcs. First, we show that abrogation of PARP-1 in the absence of telomerase does not affect the rate of telomere shortening, telomere capping, or organismal viability compared with single telomerase-deficient controls. Thus, PARP-1 does not have a major role in telomere metabolism, not even in the context of telomerase deficiency. In contrast, mice doubly deficient for telomerase and either Ku86 or DNA-PKcs manifest accelerated loss of organismal viability compared with single telomerase-deficient mice. Interestingly, this loss of organismal viability correlates with proliferative defects and age-related pathologies, but not with increased incidence of cancer. These results support the notion that absence of telomerase and short telomeres in combination with DNA repair deficiencies accelerate the aging process without impacting on tumorigenesis.
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spelling pubmed-21725872008-03-05 Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs Espejel, Silvia Klatt, Peter Murcia, Josiane Ménissier-de Martín-Caballero, Juan Flores, Juana M. Taccioli, Guillermo de Murcia, Gilbert Blasco, María A. J Cell Biol Research Articles The DNA repair proteins poly(ADP-ribose) polymerase-1 (PARP-1), Ku86, and catalytic subunit of DNA-PK (DNA-PKcs) have been involved in telomere metabolism. To genetically dissect the impact of these activities on telomere function, as well as organismal cancer and aging, we have generated mice doubly deficient for both telomerase and any of the mentioned DNA repair proteins, PARP-1, Ku86, or DNA-PKcs. First, we show that abrogation of PARP-1 in the absence of telomerase does not affect the rate of telomere shortening, telomere capping, or organismal viability compared with single telomerase-deficient controls. Thus, PARP-1 does not have a major role in telomere metabolism, not even in the context of telomerase deficiency. In contrast, mice doubly deficient for telomerase and either Ku86 or DNA-PKcs manifest accelerated loss of organismal viability compared with single telomerase-deficient mice. Interestingly, this loss of organismal viability correlates with proliferative defects and age-related pathologies, but not with increased incidence of cancer. These results support the notion that absence of telomerase and short telomeres in combination with DNA repair deficiencies accelerate the aging process without impacting on tumorigenesis. The Rockefeller University Press 2004-11-22 /pmc/articles/PMC2172587/ /pubmed/15545322 http://dx.doi.org/10.1083/jcb.200407178 Text en Copyright © 2004, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Espejel, Silvia
Klatt, Peter
Murcia, Josiane Ménissier-de
Martín-Caballero, Juan
Flores, Juana M.
Taccioli, Guillermo
de Murcia, Gilbert
Blasco, María A.
Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs
title Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs
title_full Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs
title_fullStr Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs
title_full_unstemmed Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs
title_short Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs
title_sort impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the dna repair proteins parp-1, ku86, or dna-pkcs
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172587/
https://www.ncbi.nlm.nih.gov/pubmed/15545322
http://dx.doi.org/10.1083/jcb.200407178
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