RPA and ATR link transcriptional stress to p53
RPA and ATR link transcriptional stress to p53
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DOI：
10.1073/pnas.0705317104
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发表时间：
2007-07-31
影响因子：
11.1
通讯作者：
Ljungman, Mats
中科院分区：
文献类型：
--
作者：
Derheimer, Frederick A.;O'Hagan, Heather M.;Ljungman, Mats
DNA 损伤剂触发应激反应蛋白 p53 诱导的机制尚不清楚，但可能涉及染色质结构的改变或转录或复制的阻断。在这里，我们证明转录阻断剂可以以复制独立的方式诱导 p53 Ser-15 位点的磷酸化。此外，将抗RNA聚合酶11抗体显微注射到细胞核中表明，即使在没有DNA损伤的情况下，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 核输出的减少有关；其次，特异性地抑制延伸RNA聚合酶II复合物导致p53的Ser-15位点以复制蛋白A (RPA)以及ATM和Rad3相关(ATR)依赖性方式磷酸化。我们认为，这种涉及 RPA、ATR 和 p53 的基于转录的应激反应已进化为 DNA 损伤感知机制，以保护细胞免受 DNA 损伤诱导的突变。
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, micro-injection of anti-RNA polymerase 11 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 Rad3-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.