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首页> 外文期刊>Molecular and Cellular Biology >Regulation of NuA4 Histone Acetyltransferase Activity in Transcription and DNA Repair by Phosphorylation of Histone H4
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Regulation of NuA4 Histone Acetyltransferase Activity in Transcription and DNA Repair by Phosphorylation of Histone H4

机译：在组蛋白H4磷酸化的转录和DNA修复中调节NuA4组蛋白乙酰基转移酶活性

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The NuA4 complex is a histone H4/H2A acetyltransferase involved in transcription and DNA repair. While histone acetylation is important in many processes, it has become increasingly clear that additional histone modifications also play a crucial interrelated role. To understand how NuA4 action is regulated, we tested various H4 tail peptides harboring known modifications in HAT assays. While dimethylation at arginine 3 (R3M) had little effect on NuA4 activity, phosphorylation of serine 1 (S1P) strongly decreased the ability of the complex to acetylate H4 peptides. However, R3M in combination with S1P alleviates the repression of NuA4 activity. Chromatin from cells treated with DNA damage-inducing agents shows an increase in phosphorylation of serine 1 and a concomitant decrease in H4 acetylation. We found that casein kinase 2 phosphorylates histone H4 and associates with the Rpd3 deacetylase complex, demonstrating a physical connection between phosphorylation of serine 1 and unacetylated H4 tails. Chromatin immunoprecipitation experiments also link local phosphorylation of H4 with its deacetylation, during both transcription and DNA repair. Time course chromatin immunoprecipitation data support a model in which histone H4 phosphorylation occurs after NuA4 action during double-strand break repair at the step of chromatin restoration and deacetylation. These findings demonstrate that H4 phospho-serine 1 regulates chromatin acetylation by the NuA4 complex and that this process is important for normal gene expression and DNA repair.
机译：NuA4复合物是参与转录和DNA修复的组蛋白H4 / H2A乙酰​​基转移酶。尽管组蛋白乙酰化在许多过程中都很重要，但越来越清楚的是，其他组蛋白修饰也起着至关重要的相互关联的作用。为了了解如何调节NuA4的作用，我们在HAT分析中测试了各种带有已知修饰的H4尾部肽。虽然精氨酸3（R3M）处的二甲基化对NuA4活性影响很小，但丝氨酸1（S1P）的磷酸化强烈降低了复合物将H4肽乙酰化的能力。但是，R3M与S1P组合可减轻对NuA4活性的抑制。用DNA损伤诱导剂处理过的细胞的染色质显示出丝氨酸1的磷酸化增加，同时H4乙酰化减少。我们发现酪蛋白激酶2使组蛋白H4磷酸化并与Rpd3脱乙酰基酶复合物缔合，表明丝氨酸1和未乙酰化的H4尾部的磷酸化之间存在物理联系。染色质免疫沉淀实验还将转录和DNA修复过程中H4的局部磷酸化与其脱乙酰化联系在一起。时程染色质免疫沉淀数据支持一种模型，其中在染色质恢复和脱乙酰化步骤的双链断裂修复期间，在NuA4作用后发生组蛋白H4磷酸化。这些发现表明，H4磷酸丝氨酸1通过NuA4复合物调节染色质乙酰化，并且该过程对于正常基因表达和DNA修复很重要。

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