Department of Biochemistry, Ajou University School of Medicine, Suwon, Gyeonggi, 16499, Republic of Korea.
Department of Biomedical Sciences, graduate School, Ajou University, Suwon, Gyeonggi, 16499, Republic of Korea.
Sci Rep. 2017 Jun 13;7(1):3332. doi: 10.1038/s41598-017-03211-z.
TNF receptor-associated death domain (TRADD) is an essential mediator of TNF receptor signaling, and serves as an adaptor to recruit other effectors. TRADD has been shown to cycle between the cytoplasm and nucleus due to its nuclear localization (NLS) and export sequences (NES). However, the underlying function of nuclear TRADD is poorly understood. Here we demonstrate that cytoplasmic TRADD translocates to DNA double-strand break sites (DSBs) during the DNA damage response (DDR). Deficiency of TRADD or its sequestration in cytosol leads to accumulation of γH2AX-positive foci in response to DNA damage, which is reversed by nuclear TRADD expression. TRADD facilitates non-homologous end-joining (NHEJ) by recruiting NHEJ repair factors 53BP1 and Ku70/80 complex, whereas TRADD is dispensable for homologous recombination (HR) repair. Finally, an impaired nuclear localization of TRADD triggers cell death through the persistent activation of JNK and accumulation of reactive oxygen species (ROS). Thus, our findings suggest that translocation of TRADD to DSBs into the nucleus contributes to cell survival in response to DNA damage through an activation of DNA damage repair.
肿瘤坏死因子受体相关死亡结构域（TRADD）是 TNF 受体信号转导的重要介质，作为衔接蛋白招募其他效应子。由于其核定位（NLS）和输出序列（NES），TRADD 被证明在细胞质和细胞核之间循环。然而，核 TRADD 的潜在功能尚未得到充分理解。在这里，我们证明细胞质 TRADD 在 DNA 损伤反应（DDR）期间易位到 DNA 双链断裂位点（DSB）。TRADD 或其在细胞质中的隔离缺陷会导致 DNA 损伤后γH2AX 阳性焦点的积累，而核 TRADD 的表达可逆转这种情况。TRADD 通过招募 NHEJ 修复因子 53BP1 和 Ku70/80 复合物促进非同源末端连接（NHEJ），而 TRADD 对于同源重组（HR）修复是可有可无的。最后，TRADD 的核定位受损会通过持续激活 JNK 和活性氧（ROS）的积累引发细胞死亡。因此，我们的研究结果表明，TRADD 向 DSB 的核易位有助于通过激活 DNA 损伤修复来响应 DNA 损伤的细胞存活。
