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 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.
Espejel
Silvia
S
Molecular Oncology Program, Spanish National Cancer Center (CNIO), E-28029 Madrid, Spain.
Klatt
Peter
P
Ménissier-de Murcia
Josiane
J
Martín-Caballero
Juan
J
Flores
Juana M
JM
Taccioli
Guillermo
G
de Murcia
Gilbert
G
Blasco
María A
MA
D019588:Aging, Premature / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D043171:Chromosomal Instability / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005260:Female; D000072200:Ku Autoantigen; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016615:Telomere / Q000235:genetics
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase; C000606512:Xrcc5 protein, mouse; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen