Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice - PubMed (original) (raw)

Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice

Silvia Espejel et al. EMBO Rep. 2004 May.

Abstract

Non-homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double-strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA-PK complex, formed by the Ku86/70 heterodimer and the DNA-PK catalytic subunit (DNA-PKcs). Here, we report on the detailed life-long follow-up of DNA-PKcs-defective mice. Apart from defining a role of DNA-PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA-PKcs-defective mice had a shorter life span and showed an earlier onset of ageing-related pathologies than the corresponding wild-type littermates. In addition, DNA-PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA-PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer.

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Figures

Figure 1

Figure 1

Telomere length distribution in BM cells from aged wild-type and DNA-PKcs−/− mice. One telomere fluorescence unit (TFU) corresponds to 1 kb of TTAGGG repeats. Average telomere length, standard deviation and total number of telomeres analysed from three different aged wild-type (DNA-PKcs+/+) and G1 DNA-PKcs−/− mice are shown. Numbers in parentheses identify individual mice.

Figure 2

Figure 2

TAs in BM cells from aged wild-type and G1 DNA-PKcs−/− mice. Averages of frequency of TAs per metaphase from three different aged wild-type (DNA-PKcs+/+) and DNA-PKcs−/− mice are shown.

Figure 3

Figure 3

Telomere length distribution in BM cells from wild-type and successive generations of DNA-PKcs−/− mice. One telomere fluorescence unit (TFU) corresponds to 1 kb of TTAGGG repeats. Average telomere length, standard deviation and total number of telomeres analysed from two or three different young (4–6 months) wild-type (DNA-PKcs+/+), and G1, G3 and G4 DNA-PKcs−/− mice are shown.

Figure 4

Figure 4

Telomere length determination in meiotic cells on testis sections from wild-type and successive generations of DNA-PKcs−/− mice. Average telomere fluorescence in arbitrary units (a.u.f.), standard deviation and total number of telomeres analysed from two or three different wild-type (DNA-PKcs+/+), and G1 and G4 DNA-PKcs−/− mice are shown.

Figure 5

Figure 5

TAs in BM cells from wild-type and successive generations of DNA-PKcs−/− mice. Averages of frequency of TAs per metaphase from two or three different wild-type (DNA-PKcs+/+), and G1, G3 and G4 DNA-PKcs−/− mice are shown.

Figure 6

Figure 6

Survival of wild-type and G1 DNA-PKcs−/− mice. The total number of mice from each genotype is indicated.

Figure 7

Figure 7

Pathologies of wild-type and G1 DNA-PKcs−/− mice at the time of spontaneous death at different ages: (A) percentage that presented lymphomas; (B) classification of lymphomas; (C) percentage that presented infections; and (D) percentage with intestinal atrophy. The total population for wild-type (DNA-PKcs+/+) mice was 20 animals younger than 1 year and 17 animals older than 1 year; in the case of DNA-PKcs−/− mice, 41 animals were younger than 1 year and 18 were older than 1 year. The proportion of mice that showed the specific lesion at necropsy is indicated above each bar of the graph.

Figure 8

Figure 8

Lordokyphosis in G1 DNA-PKcs−/− mice. (A) Average and standard deviation of spine angle from two 6-month-old male wild-type (DNA-PKcs+/+) and four different age-matched DNA-PKcs−/− mice are indicated. A narrowing of the angle indicates an increase in lordokyphosis. (B) Representative X-ray radiographs of 6-month-old male wild-type and DNA-PKcs−/− mice.

Figure 9

Figure 9

Growth defects in G1 DNA-PKcs−/− mice. (A) The average body weights of wild-type and DNA-PKcs−/− males and females at the indicated ages are shown. The total number of mice is indicated above each graph (numbers in parentheses) (wt, wild type, that is, DNA-PKcs+/+; ko, DNA-PKcs−/−). (B) Representative images of age-matched (6 months) male wild-type and DNA-PKcs−/− mice.

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References

    1. Bailey SM, Meyne J, Chen DJ, Kurimasa A, Li GC, Lehnert BE, Goodwin EH (1999) DNA doublestrand break repair proteins are required to cap the ends of mammalian chromosomes. Proc Natl Acad Sci USA 96: 14899–14904 - PMC - PubMed
    1. Bianchi A, de Lange T (1999) Ku binds telomeric DNA in vitro. J Biol Chem 274: 21223–21227 - PubMed
    1. Espejel S, Franco S, Rodriguez-Perales S, Bouffler SD, Cigudosa JC, Blasco MA (2002a) Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J 21: 2207–2219 - PMC - PubMed
    1. Espejel S, Franco S, Sgura A, Gae D, Bailey SM, Taccioli GE, Blasco MA (2002b) Functional interaction between DNA-PKcs and telomerase in telomere length maintenance. EMBO J 21: 6275–6287 - PMC - PubMed
    1. Gao Y, Chaudhuri J, Zhu C, Davidson L, Weaver DT, Alt FW (1998) A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Immunity 9: 367–376 - PubMed

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