ING3 is required for ATM signaling and DNA repair in response to DNA double strand breaks
ING3 is required for ATM signaling and DNA repair in response to DNA double strand breaks
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DOI：
10.1038/s41418-019-0305-x
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发表时间：
2019-11-01
影响因子：
12.4
通讯作者：
Pedeux, Remy
中科院分区：
文献类型：
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作者：
Mouche, Audrey;Archambeau, Jerome;Pedeux, Remy
生长抑制因子3（Inhibitor of Growth 3，ING3）是一种候选的抑癌基因，在肝癌、头颈部鳞状细胞癌和黑色素瘤等肿瘤中表达缺失。在本研究中，我们发现ING3缺失的人类细胞和其直系同源物YNG2缺失的酵母细胞对DNA损伤敏感，这表明在应对这种应激时具有保守的作用。在人类细胞中，ING 3被募集到DNA双链断裂处，并且是ATM激活所需的。值得注意的是，在对多柔比星的反应中，ATM激活依赖于ING3而不是TIP60，TIP60对DNA断裂的募集也依赖于ING3。这些事件导致ATM介导的NBS1磷酸化和随后的RNF8、RNF168、53BP1和BRCA1的募集，它们是DNA损伤反应的主要介质。因此，在遗传毒性胁迫下，在不存在ING3的情况下，通过非同源末端连接（NHEJ）或同源重组（HR）进行的DNA修复受损。最后，免疫球蛋白类别转换重组（CSR），一种需要NHEJ修复的生理机制，在不存在ING3的情况下受损。由于DNA双链断裂修复的失调与基因组不稳定性有关，我们提出了ING3作为参与DNA损伤信号传导和修复的看守肿瘤抑制因子的新功能。
Inhibitor of Growth 3 (ING3) is a candidate tumor suppressor gene whose expression is lost in tumors such as hepatocellular carcinoma, head and neck squamous cell carcinoma and melanoma. In the present study, we show that ING3-depleted human cells and yeast cells deleted for its ortholog YNG2 are sensitive to DNA damage suggesting a conserved role in response to such stress. In human cells, ING3 is recruited to DNA double strand breaks and is required for ATM activation. Remarkably, in response to doxorubicin, ATM activation is dependent on ING3 but not on TIP60, whose recruitment to DNA breaks also depends on ING3. These events lead to ATM-mediated phosphorylation of NBS1 and the subsequent recruitment of RNF8, RNF168, 53BP1, and BRCA1, which are major mediators of the DNA damage response. Accordingly, upon genotoxic stress, DNA repair by non-homologous end joining (NHEJ) or homologous recombination (HR) were impaired in absence of ING3. Finally, immunoglobulin class switch recombination (CSR), a physiological mechanism requiring NHEJ repair, was impaired in the absence of ING3. Since deregulation of DNA double strand break repair is associated with genomic instability, we propose a novel function of ING3 as a caretaker tumor suppressor involved in the DNA damage signaling and repair.