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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >RPA and ATR link transcriptional stress to p53
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RPA and ATR link transcriptional stress to p53

机译：RPA和ATR将转录应激与p53相关联

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摘要

The mechanisms by which DNA-damaging agents trigger the induction of the stress response protein p53 are poorly understood but may involve alterations of chromatin structure or blockage of either transcription or replication. Here we show that transcription-blocking agents can induce phosphorylation of the Ser-15 site of p53 in a replication-independent manner. Furthermore, microin-jection of anti-RNA polymerase Ⅱ antibodies into the nuclei of cells showed that blockage of transcription is sufficient for p53 accumulation even in the absence of DNA damage. This induction of p53 occurs by two independent mechanisms. First, accumulation of p53 is linked to diminished nuclear export of mRNA; and second, inhibition specifically of elongating RNA polymerase Ⅱ complexes results in the phosphorylation of the Ser-15 site of p53 in a replication protein A (RPA)- and ATM and RaD_3-related (ATR)-dependent manner. We propose that this transcription-based stress response involving RPA, ATR, and p53 has evolved as a DNA damage-sensing mechanism to safeguard cells against DNA damage-induced mutagenesis.
机译：DNA破坏剂触发应激反应蛋白p53诱导的机制了解甚少，但可能涉及染色质结构的改变或转录或复制的阻滞。在这里，我们显示了转录阻断剂可以以复制非依赖性的方式诱导p53的Ser-15位点的磷酸化。此外，将抗RNA聚合酶Ⅱ抗体显微注射到细胞核中表明，即使没有DNA损伤，转录的阻断也足以使p53积累。 p53的这种诱导通过两种独立的机制发生。首先，p53的积累与mRNA核输出减少有关。其次，特异性抑制伸长的RNA聚合酶Ⅱ复合物导致p53的Ser-15位点以复制蛋白A（RPA）和ATM以及RaD_3相关（ATR）依赖性的方式磷酸化。我们建议这种涉及RPA，ATR和p53的基于转录的应激反应已发展成为一种DNA损伤传感机制，以保护细胞免受DNA损伤诱导的诱变。

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