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首页> 美国卫生研究院文献>Molecular and Cellular Biology >DNA Excision Repair and DNA Damage-Induced Apoptosis Are Linked to Poly(ADP-Ribosyl)ation but Have Different Requirements for p53
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DNA Excision Repair and DNA Damage-Induced Apoptosis Are Linked to Poly(ADP-Ribosyl)ation but Have Different Requirements for p53

机译：DNA切除修复和DNA损伤诱导的细胞凋亡与聚（ADP-核糖基）化有关但对p53的要求不同

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Poly(ADP-ribose) polymerase (PARP) is a DNA binding zinc finger protein that catalyzes the transfer of ADP-ribose residues from NAD+ to itself and different chromatin constituents, forming branched ADP-ribose polymers. The enzymatic activity of PARP is induced upon DNA damage and the PARP protein is cleaved during apoptosis, which suggested a role of PARP in DNA repair and DNA damage-induced cell death. We have generated transgenic mice that lack PARP activity in thymocytes owing to the targeted expression of a dominant negative form of PARP. In the presence of single-strand DNA breaks, the absence of PARP activity correlated with a strongly increased rate of apoptosis compared to cells with intact PARP activity. We found that blockage of PARP activity leads to a drastic increase of p53 expression and activity after DNA damage and correlates with an accelerated onset of Bax expression. DNA repair is almost completely blocked in PARP-deficient thymocytes regardless of p53 status. We found the same increased susceptibility to apoptosis in PARP null mice, a similar inhibition of DNA repair kinetics, and the same upregulation of p53 in response to DNA damage. Thus, based on two different experimental in vivo models, we identify a direct, p53-independent, functional connection between poly(ADP-ribosyl)ation and the DNA excision repair machinery. Furthermore, we propose a p53-dependent link between PARP activity and DNA damage-induced cell death.
机译：聚（ADP-核糖）聚合酶（PARP）是一种结合DNA的锌指蛋白，可催化ADP-核糖残基从NAD + 向自身和不同染色质成分的转移，形成分支的ADP-核糖聚合物。 DNA损伤后会诱导PARP的酶活性，而PARP蛋白则在凋亡过程中被裂解，这表明PARP在DNA修复和DNA损伤诱导的细胞死亡中具有重要作用。我们已经产生了胸腺细胞中缺乏PARP活性的转基因小鼠，这是由于PARP显性负型的靶向表达所致。与具有完整PARP活性的细胞相比，在单链DNA断裂的情况下，缺乏PARP活性与凋亡率显着增加有关。我们发现，PARP活性的阻断导致DNA损伤后p53表达和活性的急剧增加，并与Bax表达的加速发作有关。无论p53状态如何，PARP缺陷胸腺细胞中的DNA修复都几乎完全被阻断。我们发现PARP null小鼠的凋亡敏感性增加相同，DNA修复动力学的抑制作用相似，并且p53对DNA损伤的响应也上调。因此，基于两种不同的体内实验模型，我们确定了聚（ADP-核糖基）化和DNA切除修复机制之间直接的，p53非依赖性的功能连接。此外，我们提出了PARP活性与DNA损伤诱导的细胞死亡之间的p53依赖性联系。

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