Programmed cell death 6, a novel p53-responsive gene, targets to the nucleus in the apoptotic response to DNA damage
Programmed cell death 6, a novel p53-responsive gene, targets to the nucleus in the apoptotic response to DNA damage
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DOI：
10.1111/j.1349-7006.2012.02362.x
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发表时间：
2012-10-01
期刊：
影响因子：
5.7
通讯作者：
Yoshida, Kiyotsugu
中科院分区：
文献类型：
--
作者：
Suzuki, Kazuho;Dashzeveg, Nurmaa;Yoshida, Kiyotsugu
细胞对遗传毒性应激的反应本质上是多方面的。在DNA损伤后，肿瘤抑制基因p53激活并在细胞周期停滞、DNA修复激活和在不可修复的损伤的情况下诱导细胞凋亡中起关键作用。细胞凋亡的破坏导致突变细胞的积累。p53依赖性细胞凋亡机制的阐明将对肿瘤患者应用该策略至关重要。然而，p53依赖性细胞凋亡的机制在很大程度上仍不清楚。在这里，我们进行了ChIP，然后进行大规模平行DNA测序分析（ChIP-seq），以揭示细胞凋亡的机制。使用ChIP-seq，我们将PDCD 6鉴定为新的p53应答基因。我们确定了假定的p53结合位点，这些位点对PDCD 6启动子区域的DNA损伤对p53调节非常重要。PDCD 6的敲低抑制p53依赖性凋亡。我们还观察到细胞色素c的释放和caspase-3对PARP的裂解被PDCD 6的耗尽所抑制。我们进一步观察到PDCD 6定位于细胞核中以响应DNA损伤。我们鉴定了PDCD 6的核定位信号，重要的是，在基因毒性应激后，PDCD 6的核积累显著诱导细胞凋亡。因此，我们得出结论，一种新的p53反应基因PDCD 6积累在细胞核中，并诱导细胞凋亡，以响应DNA损伤。
The cellular response to genotoxic stress is multifaceted in nature. Following DNA damage, the tumor suppressor gene p53 activates and plays critical roles in cell cycle arrest, activation of DNA repair and in the event of irreparable damage, induction of apoptosis. The breakdown of apoptosis causes the accumulation of mutant cells. The elucidation of the mechanism for the p53-dependent apoptosis will be crucial in applying the strategy for cancer patients. However, the mechanism of p53-dependent apoptosis remains largely unclear. Here, we carried out ChIP followed by massively parallel DNA sequencing assay (ChIP-seq) to uncover mechanisms of apoptosis. Using ChIP-seq, we identified PDCD6 as a novel p53-responsive gene. We determined putative p53-binding sites that are important for p53 regulation in response to DNA damage in the promoter region of PDCD6. Knockdown of PDCD6 suppressed p53-dependent apoptosis. We also observed that cytochrome c release and the cleavage of PARP by caspase-3 were suppressed by depletion of PDCD6. We further observed that PDCD6 localizes in the nucleus in response to DNA damage. We identified the nuclear localization signal of PDCD6 and, importantly, the nuclear accumulation of PDCD6 significantly induced apoptosis after genotoxic stress. Therefore, we conclude that a novel p53-responsive gene PDCD6 is accumulated in the nucleus and induces apoptosis in response to DNA damage.