Cellular senescence and organismal ageing in the absence of p21(CIP1/WAF1) in ku80(-/-) mice.
Ku80 is important in the repair of DNA double-strand breaks by its essential function in non-homologous end-joining. The absence of Ku80 causes the accumulation of DNA damage and leads to premature ageing in mice. We showed that mouse embryonic fibroblasts (MEFs) from ku80(-/-) mice senesced rapidly with elevated levels of p53 and p21. Deletion of p21 delayed the early senescence phenotype in ku80(-/-) MEFs, despite an otherwise intact response of p53. In contrast to ku80(-/-)p53(-/-) mice, which die rapidly primarily from lymphomas, there was no significant increase in tumorigenesis in ku80(-/-)p21(-/-) mice. However, ku80(-/-)p21(-/-) mice showed no improvement with respect to rough fur coat or osteopaenia, and even showed a shortened lifespan compared with ku80(-/-) mice. These results show that the increased lifespan of ku80(-/-) MEFs owing to the loss of p21 is not associated with an improvement of the premature ageing phenotypes of ku80(-/-) mice observed at the organismal level.
Zhao
Bo
B
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
Benson
Erica K
EK
Qiao
Ruifang
R
Wang
Xing
X
Kim
Sunchin
S
Manfredi
James J
JJ
Lee
Sam W
SW
Aaronson
Stuart A
SA
D000375:Aging / Q000502:physiology*; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016922:Cellular Senescence / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D016193:G1 Phase; D017353:Gene Deletion; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D034961:Antigens, Nuclear; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen