PARP-1 modifies the effectiveness of p53-mediated DNA damage response
PARP-1 modifies the effectiveness of p53-mediated DNA damage response
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DOI：
10.1038/sj.onc.1205169
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发表时间：
2002-02-07
期刊：
影响因子：
8
通讯作者：
Oliver, FJ
中科院分区：
文献类型：
--
作者：
Valenzuela, MT;Guerrero, R;Oliver, FJ
肿瘤抑制蛋白p53在基因毒性损伤后细胞决定停止细胞周期或进行细胞凋亡中起关键作用。p53在DNA损伤后稳定和激活，然而从DNA损伤到p53稳定和激活的信号级联事件仍然存在争议。PARP-1对不同核受体的聚（adp -核糖基化）是单链DNA损伤产生的早期事件。我们在这里提出的证据表明，PARP-1和p53之间的相互作用依赖于DNA损伤的类型。来自parp-1-/-小鼠的原代小鼠胚胎成纤维细胞与parp-1精通的细胞相比，在γ辐照后p53的积累和激活减少。另一方面。2′-甲基-2′-亚硝基-尿素（MNU）处理后，p53在parp-1缺陷细胞中快速持续积累和激活，而在parp-1 +/+细胞中几乎没有积累。IR后，p53抑制蛋白MDM-2的转换受到干扰，parp-1-/-细胞中p53丝氨酸-15磷酸化水平减弱。PARP-1在对烷基化剂的细胞毒性反应中起决定作用，但通过集落形成试验确定，它仅部分参与辐射诱导的细胞杀伤。总之，这些结果表明，PARP-1参与辐照后的p53反应，位于p53的上游，并间接调节该途径中关键底物的磷酸化水平，而MNU处理导致PARP-1缺失的细胞中p53介导的反应增强。
The tumour supressor protein p53 plays a key role in the cell's decision to arrest the cell cycle or undergo apoptosis following a genotoxic insult. p53 is stabilized and activated after DNA damage, however the cascade of events signalling from DNA lesions to p53 stabilization and activation is still controversial. Poly (ADP-ribosylation) of different nuclear acceptors by PARP-1 is an early event when a single strand DNA lesion is produced. We present here evidences that interplay between PARP-1 and p53 is dependent on the type of damage induced to DNA. Primary mouse embryonic fibroblasts derived from parp-1-/- mice exhibited decreased p53 accumulation and activation following gamma-irradiation compared to parp-1 proficient cells. On the other hand. treatment with the single alklating agent 2'-methyl-2'-nitrose-urea (MNU), resulted in the rapid and sustained accumulation and activation of p53 in parp-1-deficient cells, while very little accumulation was observed in parp-1 +/+ cells. After IR, the turnover of the p53 inhibitory protein MDM-2 is perturbed and the level of phosphorylation of p53 at serine-15 is blunted in parp-1-/- cells. PARP-1 is determinant in the cytotoxic response to alkylating agents but only partially contributes to radiation-induced cell killing, as determined by colony forming assay. Altogether, these results suggest that PARP-1 participates in the p53 response following irradiation, resides upstream of p53 and indirectly modulates the level of phosphorylation of key substrates in this pathway while treatment with MNU results in an enhanced p53-mediated response in parp-1-null cells.