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