The dynamic behavior of Ect2 in response to DNA damage.
The dynamic behavior of Ect2 in response to DNA damage.
复制标题
Ect2响应DNA损伤的动态行为
DOI：
10.1038/srep24504
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发表时间：
2016-04-14
影响因子：
4.6
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
He D;Xiang J;Li B;Liu H
Ect 2是Rho GTP酶的含BRCT的胍交换因子。它是细胞质分裂所必需的，也参与肿瘤的发生。由于大多数含有BRCT的蛋白质参与DNA损伤反应和/或DNA修复，我们测试了Ect 2是否起类似的作用。我们报告说，在原代小鼠胚胎成纤维细胞（MEFs），DNA损伤迅速导致Ect 2重新定位到染色质和DNA损伤灶样结构。Ect 2基因敲低不影响γ H2 AX、TopBP 1和Brca 1的灶性定位，也不影响Atm的激活，但它阻碍了p53 Ser 15的磷酸化和激活，导致细胞凋亡缺陷和S和G2/M检查点的激活。这些结果表明Ect 2在DNA损伤反应中起作用。有趣的是，Ect 2在DNA损伤反应的晚期被下调。虽然p53和E2 F1已被证明可以调节Ect 2的转录，但DNA损伤诱导的Ect 2下调发生在p53−/−或Atm−/− MEFs和E2 F1敲低细胞中。相反，DNA损伤诱导的Ect 2下调主要归因于蛋白质稳定性降低。与Ect 2敲低一样，Ect 2不稳定可能有助于细胞从DNA损伤反应中恢复。这些结果表明，Ect 2在DNA损伤反应的多个方面发挥作用。
Ect2 is a BRCT-containing guanidine exchange factor for Rho GTPases. It is essential for cytokinesis and is also involved in tumorigenesis. Since most BRCT-containing proteins are involved in DNA damage response and/or DNA repair, we tested whether Ect2 plays similar roles. We report that in primary mouse embryonic fibroblasts (MEFs), DNA damage quickly led to Ect2 relocalization to the chromatin and DNA damage foci-like structures. Ect2 knockdown did not affect foci localization of γH2AX, TopBP1, or Brca1, or activation of Atm, yet it impeded p53 Ser15 phosphorylation and activation and resulted in defects in apoptosis and activation of S and G2/M checkpoints in response to DNA damage. These results suggest that Ect2 plays a role in DNA damage response. Interestingly, Ect2 is down-regulated at late stages of DNA damage response. Although p53 and E2F1 have been shown to regulate Ect2 transcription, DNA damage-induced Ect2 down-regulation occurred in p53−/− or Atm−/− MEFs and E2F1 knockdown cells. Instead, DNA damage-induced Ect2 down-regulation is mainly attributable to decreased protein stability. Like Ect2 knockdown, Ect2 destabilization may help the cell to recover from DNA damage response. These results suggest that Ect2 plays roles in multiple aspects of DNA damage response.