Regulation of p53 target gene expression by peptidylarginine deiminase 4
Regulation of p53 target gene expression by peptidylarginine deiminase 4
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DOI：
10.1128/mcb.01747-07
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发表时间：
2008-08-01
影响因子：
5.3
通讯作者：
Wang, Yanming
中科院分区：
文献类型：
--
作者：
Li, Pingxin;Yao, Hongjie;Wang, Yanming
组蛋白Arg甲基化与p53靶基因的转录激活相关。然而，这种修饰是否被逆转以抑制p53靶基因的表达尚不清楚。在这里，我们报告肽基精氨酸脱亚胺酶4，组蛋白瓜氨酸酶，参与p53靶基因的抑制。PAD 4的抑制或缺失提高了p53靶基因亚组的表达，包括p21/CIP 1/WAF 1，导致细胞周期停滞和凋亡。此外，PAD 4耗竭诱导p21、细胞周期停滞和细胞凋亡是p53依赖性的。蛋白质-蛋白质相互作用研究表明p53和PAD 4之间存在相互作用。染色质免疫沉淀分析表明，PAD 4是募集到p21启动子在p53依赖的方式。RNA聚合酶II（Pol II）活性和PAD 4的缔合在UV照射期间在p21启动子处动态调节。在UV处理之前检测到暂停的RNA Pol II和高水平的PAD 4。在UV处理后的早期时间点，组蛋白Arg甲基化的增加和瓜氨酸的减少与p21的瞬时激活相关。在UV照射后的稍后时间，在p21启动子处检测到RNA Pol II的损失和PAD 4的增加。高锰酸盐足迹法进一步证实了紫外线处理后RNA Pol II活性的动态变化。总之，这些结果表明PAD 4在调节p53靶基因表达中的作用。
Histone Arg methylation has been correlated with transcriptional activation of p53 target genes. However, whether this modification is reversed to repress the expression of p53 target genes is unclear. Here, we report that peptidylarginine deiminase 4, a histone citrullination enzyme, is involved in the repression of p53 target genes. Inhibition or depletion of PAD4 elevated the expression of a subset of p53 target genes, including p21/CIP1/WAF1, leading to cell cycle arrest and apoptosis. Moreover, the induction of p21, cell cycle arrest, and apoptosis by PAD4 depletion is p53 dependent. Protein-protein interaction studies showed an interaction between p53 and PAD4. Chromatin immunoprecipitation assays showed that PAD4 is recruited to the p21 promoter in a p53-dependent manner. RNA polymerase II (Pol II) activities and the association of PAD4 are dynamically regulated at the p21 promoter during UV irradiation. Paused RNA Pol II and high levels of PAD4 were detected before UV treatment. At early time points after UV treatment, an increase of histone Arg methylation and a decrease of citrullination were correlated with a transient activation of p21. At later times after UV irradiation, a loss of RNA Pol II and an increase of PAD4 were detected at the p21 promoter. The dynamics of RNA Pol II activities after UV treatment were further corroborated by permanganate footprinting. Together, these results suggest a role of PAD4 in the regulation of p53 target gene expression.