WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors
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 DN...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-10-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/10/1258 |
| _version_ | 1827842914829467648 |
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| author | Kamila Burdova Radka Storchova Matous Palek Libor Macurek |
| author_facet | Kamila Burdova Radka Storchova Matous Palek Libor Macurek |
| author_sort | Kamila Burdova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T08:17:15Z |
| format | Article |
| id | doaj.art-cc054a673d1f4711b7a91afec9ded164 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T08:17:15Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-cc054a673d1f4711b7a91afec9ded1642023-09-02T18:48:27ZengMDPI AGCells2073-44092019-10-01810125810.3390/cells8101258cells8101258WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP InhibitorsKamila Burdova0Radka Storchova1Matous Palek2Libor Macurek3Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, CZ14220 Prague, Czech RepublicCancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, CZ14220 Prague, Czech RepublicCancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, CZ14220 Prague, Czech RepublicCancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, CZ14220 Prague, Czech RepublicGenotoxic 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.https://www.mdpi.com/2073-4409/8/10/1258dna repairphosphatasegenotoxic stresschemotherapyparp inhibitorolaparib |
| spellingShingle | Kamila Burdova Radka Storchova Matous Palek Libor Macurek WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors Cells dna repair phosphatase genotoxic stress chemotherapy parp inhibitor olaparib |
| title | WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors |
| title_full | WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors |
| title_fullStr | WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors |
| title_full_unstemmed | WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors |
| title_short | WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors |
| title_sort | wip1 promotes homologous recombination and modulates sensitivity to parp inhibitors |
| topic | dna repair phosphatase genotoxic stress chemotherapy parp inhibitor olaparib |
| url | https://www.mdpi.com/2073-4409/8/10/1258 |
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