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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.

Espejel S, Klatt P, Ménissier-de Murcia J, Martín-Caballero J, Flores JM, Taccioli G, de Murcia G, Blasco MA - J. Cell Biol. (2004)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Oncology Program, Spanish National Cancer Center (CNIO), E-28029 Madrid, Spain.

ABSTRACT
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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Effect of Ku86, DNA-PKcs, or PARP-1 deficiency on tumorigenesis and tissue atrophies in successive generations of telomerase-deficient mice. Mice with telomerase (Terc+/+) and four successive generations of telomerase-deficient (Terc−/−) mice (G1–G4) that were either wild-type (gray bars) or deficient (black bars) for Ku86 (A–C), DNA-PKcs (D–F), and PARP-1 (G–I) were killed when they showed signs of poor health and were analyzed for the occurrence of tumors (A, D, and G) as well as intestinal (B, E, and H) and testicular atrophy (C, F, and I). The number of animals suffering a given pathology in relation to the total number of animals examined is given above each bar. Significant differences (P < 0.05, Fisher's exact test) between single and double mutant animals are indicated by an asterisk; n.a. = not analyzed.
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fig3: Effect of Ku86, DNA-PKcs, or PARP-1 deficiency on tumorigenesis and tissue atrophies in successive generations of telomerase-deficient mice. Mice with telomerase (Terc+/+) and four successive generations of telomerase-deficient (Terc−/−) mice (G1–G4) that were either wild-type (gray bars) or deficient (black bars) for Ku86 (A–C), DNA-PKcs (D–F), and PARP-1 (G–I) were killed when they showed signs of poor health and were analyzed for the occurrence of tumors (A, D, and G) as well as intestinal (B, E, and H) and testicular atrophy (C, F, and I). The number of animals suffering a given pathology in relation to the total number of animals examined is given above each bar. Significant differences (P < 0.05, Fisher's exact test) between single and double mutant animals are indicated by an asterisk; n.a. = not analyzed.

Mentions: Loss of genome integrity due to impaired DNA repair or telomere dysfunction in somatic cells seriously compromises cell viability. In the context of the aging organism, the two apparently opposed biological endpoints that can result from such accumulation of DNA damage may either be increased neoplasms or, alternatively, tissue atrophy caused by a proliferative defect. To determine how, in the particular setting of telomere attrition, loss of Ku86, DNA-PKcs, and PARP-1 affects the occurrence of age-associated tumors and/or proliferative defects, we killed aged animals that showed signs of poor health, such as reduced activity or dramatic weight loss, and subjected them to exhaustive histopathological analysis (see Materials and methods). In particular, we found that in the presence of telomerase, abrogation of Ku86 did not increase tumor formation compared with wild-type controls (6.7 vs. 10.0%, P = 0.9; Fig. 3 A). Similar to Ku86 deficiency, telomere attrition caused by Terc ablation in increasing generations of Terc−/− mice did not promote tumorigenesis in these mice (Fig. 3 A). The very few preneoplastic lesions and tumors that we could observe in the different wild-type and mutant mouse colonies did not affect a particular tissue, but appeared to be randomly scattered over various organs including the liver (adenoma, hepatoma, sarcoma, and carcinoma), spleen (lymphoma and sarcoma), lung (adenoma), the skin (lipoma and subcutaneous hemangioma), the thymus (lymphoma), ovary (hemangioma), and uterus (hemangioma). Overall, there was no increase of tumor incidence with increasing generations of single Terc−/− mice compared with early generation Terc−/− mice or to wild-type controls (Fig. 3, A, D, and G). In line with our previous observation that short telomeres can act as tumor suppressors (Gonzalez-Suarez et al., 2000), comparisons of G3 Terc−/−/Ku86+/+ mice (1.5% developed tumors) with the corresponding G1 (7.8%, P = 0.05) or wild-type (10.0%, P = 0.04) cohorts revealed a significant reduction of tumors with increasing mouse generations in the absence of telomerase. The combined loss of Ku86 and telomerase in the context of critical short telomeres (G3 Ku86−/−/Terc−/−, 6.7%) did not significantly affect the incidence of tumors compared with late generation (G3) single Terc−/− cohorts (1.5%, P = 0.7; Fig. 3 A). Importantly, tumor incidence of mice doubly deficient in Ku86 and telomerase was never higher than that of the wild-type controls (Fig. 3 A), demonstrating that the combined loss of telomerase and Ku86 does not provoke neoplasms.


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

Espejel S, Klatt P, Ménissier-de Murcia J, Martín-Caballero J, Flores JM, Taccioli G, de Murcia G, Blasco MA - J. Cell Biol. (2004)

Effect of Ku86, DNA-PKcs, or PARP-1 deficiency on tumorigenesis and tissue atrophies in successive generations of telomerase-deficient mice. Mice with telomerase (Terc+/+) and four successive generations of telomerase-deficient (Terc−/−) mice (G1–G4) that were either wild-type (gray bars) or deficient (black bars) for Ku86 (A–C), DNA-PKcs (D–F), and PARP-1 (G–I) were killed when they showed signs of poor health and were analyzed for the occurrence of tumors (A, D, and G) as well as intestinal (B, E, and H) and testicular atrophy (C, F, and I). The number of animals suffering a given pathology in relation to the total number of animals examined is given above each bar. Significant differences (P < 0.05, Fisher's exact test) between single and double mutant animals are indicated by an asterisk; n.a. = not analyzed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172587&req=5

fig3: Effect of Ku86, DNA-PKcs, or PARP-1 deficiency on tumorigenesis and tissue atrophies in successive generations of telomerase-deficient mice. Mice with telomerase (Terc+/+) and four successive generations of telomerase-deficient (Terc−/−) mice (G1–G4) that were either wild-type (gray bars) or deficient (black bars) for Ku86 (A–C), DNA-PKcs (D–F), and PARP-1 (G–I) were killed when they showed signs of poor health and were analyzed for the occurrence of tumors (A, D, and G) as well as intestinal (B, E, and H) and testicular atrophy (C, F, and I). The number of animals suffering a given pathology in relation to the total number of animals examined is given above each bar. Significant differences (P < 0.05, Fisher's exact test) between single and double mutant animals are indicated by an asterisk; n.a. = not analyzed.
Mentions: Loss of genome integrity due to impaired DNA repair or telomere dysfunction in somatic cells seriously compromises cell viability. In the context of the aging organism, the two apparently opposed biological endpoints that can result from such accumulation of DNA damage may either be increased neoplasms or, alternatively, tissue atrophy caused by a proliferative defect. To determine how, in the particular setting of telomere attrition, loss of Ku86, DNA-PKcs, and PARP-1 affects the occurrence of age-associated tumors and/or proliferative defects, we killed aged animals that showed signs of poor health, such as reduced activity or dramatic weight loss, and subjected them to exhaustive histopathological analysis (see Materials and methods). In particular, we found that in the presence of telomerase, abrogation of Ku86 did not increase tumor formation compared with wild-type controls (6.7 vs. 10.0%, P = 0.9; Fig. 3 A). Similar to Ku86 deficiency, telomere attrition caused by Terc ablation in increasing generations of Terc−/− mice did not promote tumorigenesis in these mice (Fig. 3 A). The very few preneoplastic lesions and tumors that we could observe in the different wild-type and mutant mouse colonies did not affect a particular tissue, but appeared to be randomly scattered over various organs including the liver (adenoma, hepatoma, sarcoma, and carcinoma), spleen (lymphoma and sarcoma), lung (adenoma), the skin (lipoma and subcutaneous hemangioma), the thymus (lymphoma), ovary (hemangioma), and uterus (hemangioma). Overall, there was no increase of tumor incidence with increasing generations of single Terc−/− mice compared with early generation Terc−/− mice or to wild-type controls (Fig. 3, A, D, and G). In line with our previous observation that short telomeres can act as tumor suppressors (Gonzalez-Suarez et al., 2000), comparisons of G3 Terc−/−/Ku86+/+ mice (1.5% developed tumors) with the corresponding G1 (7.8%, P = 0.05) or wild-type (10.0%, P = 0.04) cohorts revealed a significant reduction of tumors with increasing mouse generations in the absence of telomerase. The combined loss of Ku86 and telomerase in the context of critical short telomeres (G3 Ku86−/−/Terc−/−, 6.7%) did not significantly affect the incidence of tumors compared with late generation (G3) single Terc−/− cohorts (1.5%, P = 0.7; Fig. 3 A). Importantly, tumor incidence of mice doubly deficient in Ku86 and telomerase was never higher than that of the wild-type controls (Fig. 3 A), demonstrating that the combined loss of telomerase and Ku86 does not provoke neoplasms.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Oncology Program, Spanish National Cancer Center (CNIO), E-28029 Madrid, Spain.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus