DNA-dependent protein kinase is not required for accumulation of p53 or cell cycle arrest after DNA damage.
DNA-dependent protein kinase is not required for accumulation of p53 or cell cycle arrest after DNA damage.
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发表时间：
1997
期刊：
影响因子：
11.2
通讯作者：
W. Rathmell;W. Kaufmann;J. Hurt;L. L. Byrd-L.;G. Chu
中科院分区：
文献类型：
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作者：
W. Rathmell;W. Kaufmann;J. Hurt;L. L. Byrd-L.;G. Chu
在对DNA损伤的反应中，细胞转导一个信号，导致p53蛋白的积累和激活，几个基因的转录诱导，包括p21、gadd45和gadd153，以及细胞周期阻滞。一种假说认为该信号是由dna依赖性蛋白激酶（DNA-PK）介导的，DNA-PK由催化亚基（DNA-PKcs）和调节亚基（Ku）组成。DNA- pk有几个特征支持这一假设：Ku与被割伤或双链断裂损伤的DNA结合，当Ku与DNA结合时，DNA- pkcs被激活，DNA- pk会在体外磷酸化p53和其他细胞周期调节蛋白，DNA- pkcs与ATM具有同源性，ATM在共济失调毛细血管扩张中发生突变，并参与p53对电离辐射反应的信号传导。通过分析DNA-PK缺乏的严重联合免疫缺陷小鼠的早期传代成纤维细胞，验证了这一假设。暴露于电离辐射、紫外线辐射或甲烷磺酸甲酯后，严重联合免疫缺陷细胞和野生型细胞的反应难以区分。在G1和G2中，p53的积累、p21、gadd45和gadd153的诱导以及细胞周期的阻滞都是正常发生的。因此，DNA损伤后p53反应或细胞周期阻滞不需要DNA- pk。
In response to DNA damage, cells transduce a signal that leads to accumulation and activation of p53 protein, transcriptional induction of several genes, including p21, gadd45, and gadd153, and cell cycle arrest. One hypothesis is that the signal is mediated by DNA-dependent protein kinase (DNA-PK), which consists of a catalytic subunit (DNA-PKcs) and a regulatory subunit (Ku). DNA-PK has several characteristics that support this hypothesis: Ku binds to DNA damaged by nicks or double-strand breaks, DNA-PKcs is activated when Ku binds to DNA, DNA-PK will phosphorylate p53 and other cell cycle regulatory proteins in vitro, and DNA-PKcs shares homology with ATM, which is mutated in ataxia telangiectasia and involved in signaling the p53 response to ionizing radiation. The hypothesis was tested by analyzing early passage fibroblasts from severe combined immunodeficient mice, which are deficient in DNA-PK. After exposure to ionizing radiation, UV radiation, or methyl methane-sulfonate, severe combined immunodeficient and wild-type cells were indistinguishable in their response. The accumulation of p53, induction of p21, gadd45, and gadd153, and arrest of the cell cycle in G1 and G2 occurred normally. Therefore, DNA-PK is not required for the p53 response or cell cycle arrest after DNA damage.