DNA damage induces downregulation of histone gene expression through the G1 checkpoint pathway
DNA damage induces downregulation of histone gene expression through the G1 checkpoint pathway
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DOI：
10.1038/sj.emboj.7600120
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发表时间：
2004-03-10
期刊：
影响因子：
11.4
通讯作者：
Zhao, JY
中科院分区：
文献类型：
--
作者：
Su, C;Gao, G;Zhao, JY
在高等真核细胞中，DNA损伤后G(1)检查点的激活导致细胞周期蛋白E-Cdk2的抑制和随后的G(1)阻滞。然而，对细胞周期蛋白E-Cdk2抑制的下游分子事件知之甚少。在这里，我们表明，除了DNA合成的抑制，电离辐射诱导下调组蛋白mRNA水平在哺乳动物细胞。这种下调发生在转录水平，需要功能性p53和p21（CIP1/WAF1）蛋白。我们证明，电离辐射诱导的DNA损伤导致NPAT的磷酸化抑制，NPAT是细胞周期蛋白E-Cdk2激酶的体内底物和组蛋白基因转录的重要调节因子，并以p53/p21依赖的方式从组蛋白基因簇中解离。在没有DNA损伤的情况下，通过特异性抑制剂抑制Cdk2活性同样会使NPAT从组蛋白基因簇中分散并抑制组蛋白基因表达。因此，我们的研究结果表明，DNA损伤后Cdk2活性的抑制通过NPAT与组蛋白基因簇的解离导致组蛋白基因转录的下调。
Activation of the G(1) checkpoint following DNA damage leads to inhibition of cyclin E-Cdk2 and subsequent G(1) arrest in higher eucaryotes. Little, however, is known about the molecular events downstream of cyclin E-Cdk2 inhibition. Here we show that, in addition to the inhibition of DNA synthesis, ionizing radiation induces downregulation of histone mRNA levels in mammalian cells. This downregulation occurs at the level of transcription and requires functional p53 and p21(CIP1/WAF1) proteins. We demonstrate that DNA damage induced by ionizing radiation results in the suppression of phosphorylation of NPAT, an in vivo substrate of cyclin E-Cdk2 kinase and an essential regulator of histone gene transcription, and its dissociation from histone gene clusters in a p53/p21-dependent manner. Inhibition of Cdk2 activity by specific inhibitors in the absence of DNA damage similarly disperses NPAT from histone gene clusters and represses histone gene expression. Our results thus suggest that inhibition of Cdk2 activity following DNA damage results in the downregulation of histone gene transcription through dissociation of NPAT from histone gene clusters.