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Published online 15 November 2004. doi:10.1083/jcb.200407178
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 4, 627-638
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Article

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

Silvia Espejel1, Peter Klatt1, Josiane Ménissier-de Murcia2, Juan Martín-Caballero1, Juana M. Flores3, Guillermo Taccioli4, Gilbert de Murcia2, and María A. Blasco1

1 Molecular Oncology Program, Spanish National Cancer Center (CNIO), E-28029 Madrid, Spain
2 Ecole Supérieure de Biotechnologie, UPR9003/CNRS, BP 10413, F-67412 Illkirch Cedex, France
3 Animal Surgery and Medicine Department, Faculty of Veterinary Medicine, Complutense University of Madrid, E-28040 Madrid, Spain
4 Department of Microbiology, Boston University, Boston, MA 02118

Correspondence to María A. Blasco: mblasco{at}cnio.es

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.

Abbreviations used in this paper: DNA-PK, DNA-dependent protein kinase; DNA-PKcs, catalytic subunit of DNA-PK; DSB, double-strand break; MEF, mouse embryonic fibroblast; NHEJ, nonhomologous end joining; PARP-1, poly(ADP-ribose) polymerase-1; Terc, telomerase RNA component.


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