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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 the life span of successive generations of telomerase-deficient mice. Overall survival of mice with intact telomerase (Terc+/+, circles) and four successive generations of telomerase-deficient (Terc−/−) mice, including G1 (squares), G2 (rhombus), G3 (upward triangles), and G4 (downward triangles), which are either wild-type (solid lines, open symbols) or deficient (dashed lines, closed symbols) for Ku86 (A), DNA-PKcs (B), or PARP-1 (C); n.a. = not analyzed.
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fig2: Effect of Ku86, DNA-PKcs, or PARP-1 deficiency on the life span of successive generations of telomerase-deficient mice. Overall survival of mice with intact telomerase (Terc+/+, circles) and four successive generations of telomerase-deficient (Terc−/−) mice, including G1 (squares), G2 (rhombus), G3 (upward triangles), and G4 (downward triangles), which are either wild-type (solid lines, open symbols) or deficient (dashed lines, closed symbols) for Ku86 (A), DNA-PKcs (B), or PARP-1 (C); n.a. = not analyzed.

Mentions: In the case of the Ku86/Terc mouse colony (Fig. 2 A), mortality at 1 yr of age in single Terc−/− mice increased from <15% in G1 and G2 to 23 and 66% in G3 and G4, respectively (Fig. 2 A, solid lines and open symbols). Similarly, we found that Ku86-deficient mice on a telomerase-positive background showed a 64% mortality at 1 yr of age, concurring with previous reports (Vogel et al., 1999). Importantly, we observed a further increase of mortality rates in mice doubly deficient for Ku86 and Terc (Terc−/−/Ku86−/−) compared with the single controls (Fig. 2 A). In particular, mortality at 1 yr of age was 79% for G1 Terc−/−/Ku86−/− mice and >90% for G2 and G3 (Fig. 2 A; dashed lines, closed symbols). In fact, in G4 Terc−/−/Ku86−/− mice the combined deficiency of telomerase and Ku86 resulted in complete extinction of the mouse colony at 7 mo of age, with a 50% mortality rate below 2 mo (Fig. 2 A). Interestingly, we have previously shown that Ku86 abrogation in the context of telomerase deficiency does not result in accelerated rate of telomere shortening with increasing mouse generations compared with single Terc-deficient controls (Espejel et al., 2002a), indicating that the synergistic effects of simultaneous Terc and Ku86 abrogation on organismal aging are not due to an accelerated rate of telomere loss. Instead, decreased survival of Terc−/−/Ku86−/− mice is likely to result from the combined effects of short telomeres due to Terc deficiency, and of increased DNA DSBs and loss of telomere protection due to Ku86 abrogation (see Discussion).


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 the life span of successive generations of telomerase-deficient mice. Overall survival of mice with intact telomerase (Terc+/+, circles) and four successive generations of telomerase-deficient (Terc−/−) mice, including G1 (squares), G2 (rhombus), G3 (upward triangles), and G4 (downward triangles), which are either wild-type (solid lines, open symbols) or deficient (dashed lines, closed symbols) for Ku86 (A), DNA-PKcs (B), or PARP-1 (C); n.a. = not analyzed.
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Related In: Results  -  Collection

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

fig2: Effect of Ku86, DNA-PKcs, or PARP-1 deficiency on the life span of successive generations of telomerase-deficient mice. Overall survival of mice with intact telomerase (Terc+/+, circles) and four successive generations of telomerase-deficient (Terc−/−) mice, including G1 (squares), G2 (rhombus), G3 (upward triangles), and G4 (downward triangles), which are either wild-type (solid lines, open symbols) or deficient (dashed lines, closed symbols) for Ku86 (A), DNA-PKcs (B), or PARP-1 (C); n.a. = not analyzed.
Mentions: In the case of the Ku86/Terc mouse colony (Fig. 2 A), mortality at 1 yr of age in single Terc−/− mice increased from <15% in G1 and G2 to 23 and 66% in G3 and G4, respectively (Fig. 2 A, solid lines and open symbols). Similarly, we found that Ku86-deficient mice on a telomerase-positive background showed a 64% mortality at 1 yr of age, concurring with previous reports (Vogel et al., 1999). Importantly, we observed a further increase of mortality rates in mice doubly deficient for Ku86 and Terc (Terc−/−/Ku86−/−) compared with the single controls (Fig. 2 A). In particular, mortality at 1 yr of age was 79% for G1 Terc−/−/Ku86−/− mice and >90% for G2 and G3 (Fig. 2 A; dashed lines, closed symbols). In fact, in G4 Terc−/−/Ku86−/− mice the combined deficiency of telomerase and Ku86 resulted in complete extinction of the mouse colony at 7 mo of age, with a 50% mortality rate below 2 mo (Fig. 2 A). Interestingly, we have previously shown that Ku86 abrogation in the context of telomerase deficiency does not result in accelerated rate of telomere shortening with increasing mouse generations compared with single Terc-deficient controls (Espejel et al., 2002a), indicating that the synergistic effects of simultaneous Terc and Ku86 abrogation on organismal aging are not due to an accelerated rate of telomere loss. Instead, decreased survival of Terc−/−/Ku86−/− mice is likely to result from the combined effects of short telomeres due to Terc deficiency, and of increased DNA DSBs and loss of telomere protection due to Ku86 abrogation (see Discussion).

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