WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors
WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors
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DOI：
10.3390/cells8101258
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发表时间：
2019-10-01
期刊：
影响因子：
6
通讯作者：
Macurek, Libor
中科院分区：
文献类型：
--
作者：
Burdova, Kamila;Storchova, Radka;Macurek, Libor
基因毒性应激触发 DNA 修复和细胞周期检查点途径的联合作用。蛋白磷酸酶 2C delta（称为 WIP1）通过抑制 p53 和染色质其他靶标的功能来及时失活 DNA 损伤反应。在这里，我们证明 WIP1 通过同源重组促进 DNA 修复。 WIP1 的丢失或抑制延迟了 S/G2 细胞中电离辐射诱导的 53BP1 灶的消失并促进了细胞死亡。我们将乳腺癌相关蛋白 1 (BRCA1) 确定为 WIP1 的相互作用子和底物，并证明 WIP1 活性对于 BRCA1 招募到 DNA 病变侧翼染色质的正确动态是必需的。此外，WIP1 在苏氨酸 543 处使 53BP1 去磷酸化，而苏氨酸 543 先前被认为参与介导与 RIF1 的相互作用。最后，我们报告说，抑制 WIP1 会导致 S/G2 细胞中 DNA 损伤累积，并增加癌细胞对聚（ADP-核糖）聚合酶抑制剂奥拉帕尼的敏感性。我们认为抑制 WIP1 可能会增加 BRCA1 丰富的癌细胞对奥拉帕尼的敏感性。
Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.