Candéias S M, Durum S K, Muegge K
Intramural Research Support Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Biochimie. 1997 Oct;79(9-10):607-12. doi: 10.1016/s0300-9084(97)82010-x.
The recruitment and activation of DNA-repair mechanisms at the sites of DNA-damage after exposure of cells to genotoxic stress are poorly understood. The DNA-dependent kinase (DNA-PK) was considered to be a likely candidate for initiating these events because of the conditions required for its activation, its phosphorylation of p53 in vitro and the extreme radiosensitivity induced by its inactivation in vivo. We analyzed irradiation-induced p53-activation in SCID mice, which lack DNA-PK activity, and found that p53-dependent apoptosis and p21waf/cip1/sdi1 transcription in these animals are at least as efficient as in wild-type mice. Thus, our results show that DNA-PK is not the main sensor for genotoxic stress and is not required for p53 activation. In fact, they rather suggest that DNA-PK may play a role in p53 down-regulation.
细胞暴露于基因毒性应激后，DNA损伤位点处DNA修复机制的募集和激活目前仍知之甚少。由于DNA依赖性蛋白激酶（DNA-PK）的激活所需条件、其在体外对p53的磷酸化作用以及其在体内失活所诱导的极端放射敏感性，它被认为是启动这些事件的一个可能候选因素。我们分析了缺乏DNA-PK活性的SCID小鼠中辐射诱导的p53激活情况，发现这些动物中p53依赖性凋亡和p21waf/cip1/sdi1转录至少与野生型小鼠一样有效。因此，我们的结果表明，DNA-PK不是基因毒性应激的主要传感器，p53激活也不需要它。事实上，结果反而表明DNA-PK可能在p53下调中起作用。
