Deletion of Ku86 causes early onset of senescence in mice.
DNA double-strand breaks formed during the assembly of antigen receptors or after exposure to ionizing radiation are repaired by proteins important for nonhomologous end joining that include Ku86, Ku70, DNA-PK(CS), Xrcc4, and DNA ligase IV. Here we show that ku86-mutant mice, compared with control littermates, prematurely exhibited age-specific changes characteristic of senescence that include osteopenia, atrophic skin, hepatocellular degeneration, hepatocellular inclusions, hepatic hyperplastic foci, and age-specific mortality. Cancer and likely sepsis (indicated by reactive immune responses) partly contributed to age-specific mortality for both cohorts, and both conditions occurred earlier in ku86(-/-) mice. These data indicate that Ku86-dependent chromosomal metabolism is important for determining the onset of age-specific changes characteristic of senescence in mice.
Vogel
H
H
Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Lim
D S
DS
Karsenty
G
G
Finegold
M
M
Hasty
P
P
D000367:Age Factors; D000375:Aging / Q000235:genetics*; D000818:Animals; D034961:Antigens, Nuclear; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D004838:Epiphyses / Q000033:anatomy & histology / Q000378:metabolism; D017353:Gene Deletion; D000072200:Ku Autoantigen; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012867:Skin / Q000033:anatomy & histology / Q000378:metabolism; D013131:Spine / Q000033:anatomy & histology / Q000378:metabolism
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D004247:DNA; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606512:Xrcc5 protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen