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. 2007 Dec;27(23):8205-14.
doi: 10.1128/MCB.00785-07. Epub 2007 Sep 17.

Deletion of Ku70, Ku80, or Both Causes Early Aging Without Substantially Increased Cancer

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Free PMC article

Deletion of Ku70, Ku80, or Both Causes Early Aging Without Substantially Increased Cancer

Han Li et al. Mol Cell Biol. .
Free PMC article

Abstract

Ku70 forms a heterodimer with Ku80, called Ku, that is critical for repairing DNA double-stand breaks by nonhomologous end joining and for maintaining telomeres. Mice with either gene mutated exhibit similar phenotypes that include increased sensitivity to ionizing radiation and severe combined immunodeficiency. However, there are also differences in the reported phenotypes. For example, only Ku70 mutants are reported to exhibit a high incidence of thymic lymphomas while only Ku80 mutants are reported to exhibit early aging with very low cancer levels. There are two explanations for these differences. First, either Ku70 or Ku80 functions outside the Ku heterodimer such that deletion of one is not identical to deletion of the other. Second, divergent genetic backgrounds or environments influence the phenotype. To distinguish between these possibilities, the Ku70 and Ku80 mutations were crossed together to generate Ku70, Ku80, and double-mutant mice in the same genetic background raised in the same environment. We show that these three cohorts have similar phenotypes that most resemble the previous report for Ku80 mutant mice, i.e., early aging without substantially increased cancer levels. Thus, our observations suggest that the Ku heterodimer is important for longevity assurance in mice since divergent genetic backgrounds and/or environments likely account for these previously reported differences.

Figures

FIG. 1.
FIG. 1.
Life span analysis. Survival curves (100% × number of mice alive after each week/total number of mice at 3 weeks) are shown. Mice in the first 3 weeks were not included since Ku mutant mice often die before weaning because they are unable to compete with their littermates. Which line colors represent which mouse strains is shown in the inset (numbers of mice observed are in parentheses).
FIG. 2.
FIG. 2.
External ageing characteristics. (A) Gross aging seen in control (Con), ku70−/−, ku80−/−, and ku80−/− ku70−/− (double mutant, DM) littermates. Red arrows point to kyphosis. Increased magnifications of an old control mouse (>120 weeks old) show suppurative conjunctivitis (B), rough fur coat (C), rectal prolapse (D), paraphimosis (E), and alopecia (F) (dorsal view of cranium, neck, and thorax). The graphs show the onset and incidence of kyphosis (G), rough fur coat (H), alopecia (I), paraphimosis (J), rectal prolapse (K), and suppurative conjunctivitis (L). Statistical analysis based on a t test comparing the groups listed in Table 1: 1 versus 5 and 1 versus 9, P = 1.0 (all phenotypes); 1 versus 13, P = 0.06 (kyphosis, rough fur, and alopecia) and P = 1.0 (the remaining phenotypes); 1 versus 17, <0.001 (kyphosis and rough fur), P = 0.02 (alopecia), P = 0.006 (suppurative conjunctivitis), P = 0.11 (paraphimosis), and P = 1.0 (rectal prolapse); 1 versus 18, P < 0.001 (kyphosis), P < 0.002 (rough fur), P = 0.31 (alopecia), P = 0.01 (suppurative conjunctivitis), and P = 1.0 (rectal prolapse); 2, 3, and 4 versus 6, 7, and 8, P = 0.02 (kyphosis), P = 0.09 (rough fur), P = 0.21 (alopecia), P = 0.09 (suppurative conjunctivitis), P = 0.23 (paraphimosis), and P = 0.21 (rectal prolapse); 2, 3, and 4 versus 10, 11, and 12, P < 0.001 (kyphosis, rough fur, and suppurative conjunctivitis), P = 0.02 (alopecia), P = 0.002 (paraphimosis), and P = 0.008 (rectal prolapse); 2, 3, and 4 versus 14, 15, and 16, P < 0.001 (all phenotypes).
FIG. 3.
FIG. 3.
Microscopic analysis. (A) Eight-week-old control (Con) and mutant femurs. Double mutant, DM. Top images, distal femur; bottom images, section of epiphysis from the boxed insets. Note that the chondrocytes are aligned in a series of columns, as highlighted by the oval for the control. (B) Fifty- to 60-week-old control and mutant mice. Note that the columns of chondrocytes are diminished in the control and mostly gone in the mutants. Also note that the cortical wall is thinner with fewer trabeculae in the mutants but not in the control. (C) Control at >120 weeks. The columns of chondrocytes are mostly gone. The cortical wall is thinner with fewer trabeculae compared to earlier time points. (D) Diagram showing the section of cortical wall (proximal to the epiphysis), trabeculae (between the epiphysis and articular surface), and epiphysis (the entire length) used to measure age-related changes. See Materials and Methods for the quantification methods used. (E) Graphs displaying the age-related changes in surface area for the cortical wall (left), trabeculae (middle), and epiphysis (right). There are three mice in each group, and shown is the surface area (SA) relative to the mean of the 8-week-old control (hence, the 8-week-old control is always 1.0). Statistical analysis based on a t test: 8-week-old control versus 50- to 60-week-old control, P = 0.9624 (cortical wall), P = 0.2707 (trabeculae), and P = 0.9251 (epiphysis); 8-week-old control versus >120-week-old control, P = 0.0036 (cortical wall), P = 0.0621 (trabeculae), and P = 0.0003 (epiphysis); 8-week-old mutants combined versus 50- to 60-week-old mutants combined, P = 0.00081 (cortical wall), P = 0.00739 (trabeculae), and P = 0.00158 (epiphysis).
FIG. 4.
FIG. 4.
Chromosomal abnormalities observed by two-color FISH on metaphase spreads. (A) Representative examples of chromosomal abnormalities. Shown are the DAPI stain, telomere probe (telo), and merge. The white arrow points to a chromosomal fragment. Con, control. (B to E) Graphs showing the total number of events per total number of metaphase spreads for single-chromatid telomere loss (B), fragments/breaks (C), telomere associations (D), and telomere fusions (E). The number may be greater than 1 if enough metaphase spreads have multiple events (see Table 2). Statistical analysis based on the likelihood ratio test comparing groups listed in Table 2: 1 versus 2, 3, and 4, P = 0.0513 (single-chromatid telomere loss), P < 0.0001 (fragments/breaks), P = 0.4469 (telomere associations), and P < 0.0001 (telomere fusions); 1 versus 5, P = 0.3570 (single-chromatid telomere loss), P < 0.3141 (fragments/breaks), P = 0.3338 (telomere associations), and P = 0.2814 (telomere fusions); 1 versus 9, P < 0.0001 (single-chromatid telomere loss), P = 0.0017 (fragments/breaks), P < 0.0001 (telomere associations), and P = 0.2959 (telomere fusions); 2, 3, and 4 versus 6, 7, and 8, P < 0.0001 (single-chromatid telomere loss), P < 0.0419 (fragments/breaks), P < 0.0001 (telomere associations), and P = 0.5530 (telomere fusions).

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