Zhao Bo, Benson Erica K, Qiao Ruifang, Wang Xing, Kim Sunchin, Manfredi James J, Lee Sam W, Aaronson Stuart A
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
EMBO Rep. 2009 Jan;10(1):71-8. doi: 10.1038/embor.2008.220. Epub 2008 Dec 12.
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.
Ku80在DNA双链断裂修复中起着重要作用，它在非同源末端连接中发挥着关键功能。Ku80的缺失会导致DNA损伤的积累，并致使小鼠过早衰老。我们发现，来自ku80(-/-)小鼠的小鼠胚胎成纤维细胞（MEF）会迅速衰老，同时p53和p21水平升高。p21的缺失延缓了ku80(-/-) MEF的早期衰老表型，尽管p53的反应在其他方面保持完整。与ku80(-/-)p53(-/-)小鼠主要因淋巴瘤迅速死亡不同，ku80(-/-)p21(-/-)小鼠的肿瘤发生并没有显著增加。然而，ku80(-/-)p21(-/-)小鼠在粗糙的皮毛或骨质减少方面没有改善，甚至与ku80(-/-)小鼠相比寿命缩短。这些结果表明，由于p21缺失导致ku80(-/-) MEF寿命延长，这与在整体水平观察到的ku80(-/-)小鼠过早衰老表型的改善无关。
