DNA damage signaling induced by the G-quadruplex ligand 12459 is modulated by PPM1D/WIP1 phosphatase.
DNA damage signaling induced by the G-quadruplex ligand 12459 is modulated by PPM1D/WIP1 phosphatase.
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DOI：
10.1093/nar/gkt073
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发表时间：
2013-04-01
影响因子：
14.9
通讯作者：
Riou JF
中科院分区：
文献类型：
--
作者：
Douarre C;Mergui X;Sidibe A;Gomez D;Alberti P;Mailliet P;Trentesaux C;Riou JF
三嗪衍生物12459是一种有效的G-四链配体，随着其浓度和作用于细胞的时间的变化，它会触发细胞凋亡或延迟生长停滞、端粒缩短和G-悬臂降解。我们研究了12459对A549细胞的DNA损伤反应。亚微摩尔浓度为12459会触发延迟的Chk1-ATR介导的DNA损伤反应，与端粒功能障碍和G2/M期停滞相关。令人惊讶的是，增加12459的浓度导致细胞凋亡，诱导了一种绕过DNA损伤信号并导致Chk1和γ-H2Ax去磷酸化的机制。我们发现磷酸酶蛋白磷酸酶镁依赖的1D/野生型P53诱导的磷酸酶(PPM1D/Wip1)是导致这种去磷酸化的一个因素。SiRNA介导的PPM1D/Wip1缺失使DNA损伤信号重新激活了12459。此外，PPM1D/WIP1还被12459诱导的ROS激活。12459产生的ROS足以在PPM1D/WIP1耗尽时引发A549细胞的早期DNA损伤。然而，N-乙酰半胱氨酸处理的ROS失活并不改变12459诱导的细胞凋亡反应。由于PPM1D的表达最近被报道调节DNA修复分子的招募，我们的数据表明对12459的无效保护周期，从而导致细胞死亡的延迟机制。
The triazine derivative 12459 is a potent G-quadruplex ligand that triggers apoptosis or delayed growth arrest, telomere shortening and G-overhang degradation, as a function of its concentration and time exposure to the cells. We have investigated here the DNA damage response induced by 12459 in A549 cells. Submicromolar concentrations of 12459 triggers a delayed Chk1-ATR–mediated DNA damage response associated with a telomeric dysfunction and a G2/M arrest. Surprisingly, increasing concentrations of 12459 leading to cell apoptosis induced a mechanism that bypasses the DNA damage signaling and leads to the dephosphorylation of Chk1 and γ-H2AX. We identified the phosphatase Protein Phosphatase Magnesium dependent 1D/Wild-type P53-Induced Phosphatase (PPM1D/WIP1) as a factor responsible for this dephosphorylation. SiRNA-mediated depletion of PPM1D/WIP1 reactivates the DNA damage signaling by 12459. In addition, PPM1D/WIP1 is activated by reactive oxygen species (ROS) induced by 12459. ROS generated by 12459 are sufficient to trigger an early DNA damage in A549 cells when PPM1D/WIP1 is depleted. However, ROS inactivation by N-acetyl cysteine (NAC) treatment does not change the apoptotic response induced by 12459. Because PPM1D expression was recently reported to modulate the recruitment of DNA repair molecules, our data would suggest a cycle of futile protection against 12459, thus leading to a delayed mechanism of cell death.
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影响因子：
4.3
作者：
Meek, David W.;Cox, Miranda
通讯作者：
Cox, Miranda
DOI：
10.1126/science.1170633
发表时间：
2009-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
de Lange T
通讯作者：
de Lange T
DOI：
10.1073/pnas.94.12.6048
发表时间：
1997-06-10
影响因子：
11.1
作者：
Fiscella, M;Zhang, HL;Appella, E
通讯作者：
Appella, E
影响因子：
8
作者：
Jackson, MW;Agarwal, MK;Stark, GR
通讯作者：
Stark, GR
影响因子：
16
作者：
Lu, XB;Bocangel, D;Donehower, LA
通讯作者：
Donehower, LA