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WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors
K. Burdova, R. Storchova, M. Palek, L. Macurek,
Language English Country Switzerland
Document type Journal Article, Research Support, Non-U.S. Gov't
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PubMed
31619012
DOI
10.3390/cells8101258
Knihovny.cz E-resources
- MeSH
- Tumor Suppressor p53-Binding Protein 1 metabolism MeSH
- Apoptosis drug effects MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Chromatin metabolism MeSH
- Phthalazines pharmacology MeSH
- HEK293 Cells MeSH
- Homologous Recombination genetics MeSH
- G2 Phase Cell Cycle Checkpoints MeSH
- S Phase Cell Cycle Checkpoints MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms metabolism MeSH
- DNA Repair genetics physiology MeSH
- Poly(ADP-ribose) Polymerase Inhibitors pharmacology MeSH
- Piperazines pharmacology MeSH
- DNA Damage genetics physiology MeSH
- Cell Proliferation drug effects MeSH
- BRCA1 Protein metabolism MeSH
- Protein Phosphatase 2C antagonists & inhibitors genetics metabolism MeSH
- Antineoplastic Agents pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
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