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The p53 Response to DNA Damage In Vivo Is Independent of DNA-Dependent Protein Kinase

机译：体内对DNA损伤的p53反应独立于DNA依赖性蛋白激酶。

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Ionizing radiation (IR) exposure causes mammalian cells to undergo p53-dependent cell cycle arrest and/or apoptosis. The in vivo role of DNA-dependent protein kinase (DNA-PK) in the transduction of the DNA damage signal to p53 remains unresolved. To determine the relationship between DNA-PK and p53, we studied the cell cycle and apoptotic responses to IR in mice deficient in DNA-PK. Using the slipmouse, which harbors an inactivating mutation of the DNA-PK catalytic subunit (DNA-PKcs), we demonstrated not only that these DNA-PKcs null mutants were highly radiosensitive but also that upon IR treatment, p53 accumulated in their cultured cells and tissue. Induced p53 was transcriptionally active and mediated the induction of p21 and Bax inslip cells. Examination of the thymic cell cycle response to IR treatment indicated that the slipG1/S-phase cell cycle checkpoint function was intact. We further show that slip mice exhibited a higher level of spontaneous thymic apoptosis as well as a more robust apoptotic response to IR than wild-type mice. Together, these data demonstrate that the p53-mediated response to DNA damage is intact in cells devoid of DNA-PK activity and suggest that other kinases, such as the product of the gene (ATM) mutated in ataxia telangiectasia, are better candidates for regulating IR-induced phosphorylation and accumulation of p53.
机译：电离辐射（IR）暴露会导致哺乳动物细胞经历p53依赖性细胞周期停滞和/或凋亡。 DNA依赖性蛋白激酶（DNA-PK）在将DNA损伤信号转导至p53中的体内作用仍未确定。为了确定DNA-PK和p53之间的关系，我们研究了DNA-PK缺陷小鼠的细胞周期和对IR的凋亡反应。使用具有DNA-PK催化亚基（DNA-PKcs）失活突变的 slip 小鼠，我们不仅证明了这些DNA-PKcs无效突变体具有高度放射敏感性，而且还证明了经过IR处理后，p53积累在其培养的细胞和组织中。诱导的p53具有转录活性，并介导滑动细胞中p21和Bax的诱导。胸腺细胞周期对IR处理的反应表明， slip G 1 / S期细胞周期检查点功能完好无损。我们进一步表明，与野生型小鼠相比， slip 小鼠表现出更高的自发胸腺细胞凋亡水平以及对IR的更强的凋亡反应。总之，这些数据表明在没有DNA-PK活性的细胞中，p53介导的对DNA损伤的反应是完整的，并表明其他激酶，例如在共济失调毛细血管扩张症中突变的基因产物（ATM），是更好的调节候选物。 IR诱导的p53磷酸化和积累。

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