Orphan Receptor TR3 Enhances p53 Transactivation and Represses DNA Double-Strand Break Repair in Hepatoma Cells under Ionizing Radiation
Orphan Receptor TR3 Enhances p53 Transactivation and Represses DNA Double-Strand Break Repair in Hepatoma Cells under Ionizing Radiation
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孤儿受体 TR3 增强电离辐射下肝癌细胞中 p53 反式激活并抑制 DNA 双链断裂修复
DOI：
10.1210/me.2011-0081
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发表时间：
2011-08-01
影响因子：
--
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
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作者：
Zhao, Bi-xing;Chen, Hang-zi;Wu, Qiao
响应于电离辐射（IR）诱导的DNA双链断裂（DSB），细胞引发进化上保守的检查点响应，其诱导细胞周期停滞和DNA修复或凋亡，从而维持基因组稳定性。DNA依赖性蛋白激酶（DNA-PK）是参与哺乳动物细胞DSB修复的中心酶，其包含DNA-PK催化亚基和Ku蛋白，其充当调节元件。DNA-PK也作为一种信号分子，选择性地调节p53依赖性细胞凋亡的IR。在这里，我们证明了孤儿核受体TR 3通过阻断Ku 80 DNA末端结合活性和促进肝癌细胞中DNA-PK诱导的p53活性来抑制DSB修复。我们发现TR 3与Ku 80相互作用并抑制其与DNA末端的结合，从而抑制DSB修复。此外，TR 3是DNA-PK的磷酸化底物，并以Ku 80非依赖性方式与DNA-PK催化亚基相互作用。磷酸化的TR 3反过来增强DNA-PK诱导的磷酸化和p53转录活性，从而增强IR诱导的肝癌细胞凋亡。总之，我们的研究结果揭示了TR 3的新功能，不仅在DSB修复调节中，而且在IR诱导的肝癌细胞凋亡中，他们表明TR 3是癌症放疗的潜在靶点。（分子内分泌学25：1337-1350，2011）
In response to ionizing radiation (IR)-induced DNA double-strand breaks (DSB), cells elicit an evolutionarily conserved checkpoint response that induces cell cycle arrest and either DNA repair or apoptosis, thereby maintaining genomic stability. DNA-dependent protein kinase (DNA-PK) is a central enzyme involved in DSB repair for mammalian cells that comprises a DNA-PK catalytic subunit and the Ku protein, which act as regulatory elements. DNA-PK also functions as a signaling molecule to selectively regulate p53-dependent apoptosis in response to IR. Herein, we demonstrate that the orphan nuclear receptor TR3 suppresses DSB repair by blocking Ku80 DNA-end binding activity and promoting DNA-PK-induced p53 activity in hepatoma cells. We find that TR3 interacts with Ku80 and inhibits its binding to DNA ends, which then suppresses DSB repair. Furthermore, TR3 is a phosphorylation substrate for DNA-PK and interacts with DNA-PK catalytic subunit in a Ku80-independent manner. Phosphorylated TR3, in turn, enhances DNA-PK-induced phosphorylation and p53 transcription activity, thereby enhancing IR-induced apoptosis in hepatoma cells. Together, our findings reveal novel functions for TR3, not only in DSB repair regulation but also in IR-induced hepatoma cell apoptosis, and they suggest that TR3 is a potential target for cancer radiotherapy. (Molecular Endocrinology 25: 1337-1350, 2011)