Nedd4 Family Interacting Protein 1 (Ndfip1) Is Required for Ubiquitination and Nuclear Trafficking of BRCA1-associated ATM Activator 1 (BRAT1) during the DNA Damage Response
Nedd4 Family Interacting Protein 1 (Ndfip1) Is Required for Ubiquitination and Nuclear Trafficking of BRCA1-associated ATM Activator 1 (BRAT1) during the DNA Damage Response
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DOI：
10.1074/jbc.m114.613687
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发表时间：
2015-03-13
影响因子：
4.8
通讯作者：
Tan, Seong-Seng
中科院分区：
文献类型：
--
作者：
Low, Ley-Hian;Chow, Yuh-Lit;Tan, Seong-Seng
在损伤期间，细胞易受多种应激条件的凋亡，包括导致双链断裂的DNA损伤。如果没有修复，这些断裂会导致DNA复制和转录的畸变，从而导致细胞凋亡。对DNA损伤的主要反应是由蛋白激酶ATM（共济失调毛细血管扩张突变）提供的，其能够指挥过多的用于DNA修复、细胞周期停滞甚至凋亡的信号网络。DNA损伤反应中的一个关键因素是激活蛋白质进入细胞核以修复受损的DNA。BRAT1是这些蛋白质中的一种，它通过维持其磷酸化状态同时也保持其他磷酸酶在海湾中作为ATM的激活剂发挥作用。然而，目前还不清楚BRAT 1是如何被运输到细胞核中以维持ATM磷酸化的。在这里，我们证明了Ndfip1介导的BRAT 1泛素化导致BRAT 1贩运到细胞核。在没有Ndfip1的情况下，BRAT1不能易位到细胞核。在遗传毒性应激下，细胞表现出Ndfip1和磷酸化ATM的表达增加。脑损伤后，神经元显示Ndlip 1表达增加和BRATE核转位。这些结果表明，Ndfip 1作为细胞损伤期间的传感器蛋白，Ndfip 1上调作为Nedd4 E3连接酶引起BRAT1泛素化的线索，随后是BRAT1核转位。
During injury, cells are vulnerable to apoptosis from a variety of stress conditions including DNA damage causing double-stranded breaks. Without repair, these breaks lead to aberrations in DNA replication and transcription, leading to apoptosis. A major response to DNA damage is provided by the protein kinase ATM (ataxia telangiectasia mutated) that is capable of commanding a plethora of signaling networks for DNA repair, cell cycle arrest, and even apoptosis. A key element in the DNA damage response is the mobilization of activating proteins into the cell nucleus to repair damaged DNA. BRAT1 is one of these proteins, and it functions as an activator of ATM by maintaining its phosphorylated status while also keeping other phosphatases at bay. However, it is unknown how BRAT1 is trafficked into the cell nucleus to maintain ATM phosphorylation. Here we demonstrate that Ndfip1-mediated ubiquitination of BRAT1 leads to BRAT1 trafficking into the cell nucleus. Without Ndfip1, BRAT1 failed to translocate to the nucleus. Under genotoxic stress, cells showed increased expression of both Ndfip1 and phosphorylated ATM. Following brain injury, neurons show increased expression of Ndlip1 and nuclear translocation of BRATE These results point to Ndfip1 as a sensor protein during cell injury and Ndfip1 up-regulation as a cue for BRAT1 ubiquitination by Nedd4 E3 ligases, followed by nuclear translocation of BRAT1.