title: DNA damage signaling induced by the G-quadruplex ligand 12459 is modulated by PPM1D/WIP1 phosphatase.
abstract: 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.
authors: Laboratoire d'Onco-pharmacologie, JE 2428, Université de Reims, 51 rue Cognacq Jay, 51096 Reims cedex, France.
authors: Céline
authors: C
authors: Douarre
authors: Xénia
authors: X
authors: Mergui
authors: Assitan
authors: A
authors: Sidibe
authors: Dennis
authors: D
authors: Gomez
authors: Patrizia
authors: P
authors: Alberti
authors: Patrick
authors: P
authors: Mailliet
authors: Chantal
authors: C
authors: Trentesaux
authors: Jean-François
authors: JF
authors: Riou
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D016922:Cellular Senescence; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D011806:Quinolinium Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016615:Telomere / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C480235:G-quadruplex ligand 12459; D011806:Quinolinium Compounds; D017382:Reactive Oxygen Species; D014227:Triazines; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
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