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首页> 外文期刊>Molecular and Cellular Biology >Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4
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Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4

机译：肽基精氨酸脱亚氨酶4对p53靶基因表达的调控

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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.
机译：组蛋白Arg甲基化已与p53靶基因的转录激活相关。但是，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，我们报告说，肽基丝氨酸精氨酸脱亚氨酶4，一种组蛋白瓜氨酸化酶，参与了p53靶基因的抑制。 PAD4的抑制或耗竭提高了p53靶基因（包括p21 / CIP1 / WAF1）的子集的表达，导致细胞周期停滞和凋亡。此外，PAD4耗尽对p21的诱导，细胞周期停滞和凋亡均依赖于p53。蛋白质相互作用研究显示p53和PAD4之间存在相互作用。染色质免疫沉淀试验表明，PAD4以p53依赖性方式募集到p21启动子。 RNA聚合酶II（Pol II）活性和PAD4的缔合在紫外线照射过程中在p21启动子上受到动态调节。在进行紫外线处理之前，检测到RNA聚合酶II暂停和高水平的PAD4。在紫外线处理后的早期时间点，组蛋白Arg甲基化的增加和瓜氨酸化的减少与p21的瞬时活化有关。在紫外线照射后的晚些时候，在p21启动子处检测到RNA Pol II的缺失和PAD4的增加。高锰酸盐足迹进一步证实了紫外线处理后RNA Pol II活性的动态。在一起，这些结果表明PAD4在p53靶基因表达的调节中的作用。

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