DNA repair network analysis reveals shielding as a key regulator of NEHJ and PARP inhibitor sensitivity
| Autor: | Rajat Gupta, Takeo Narita, Elina Maskey, Jiri Lukas, André Nussenzweig, Chunaram Choudhary, Kumar Somyajit, Dimitris Typas, Andre Stanlie, Magdalena Kremer, Michael Lammers, Niels Mailand |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
DNA End-Joining Repair DNA Repair Regulator Cell Cycle Proteins Telomere-Binding Proteins/antagonists & inhibitors RNA Small Interfering/metabolism chemistry.chemical_compound 0302 clinical medicine DNA-Binding Proteins/antagonists & inhibitors DNA Breaks Double-Stranded RNA Small Interfering BRCA1 Protein Effector Nuclear Proteins Poly(ADP-ribose) Polymerase Inhibitors/pharmacology Cell biology DNA End-Joining Repair/drug effects DNA-Binding Proteins 030220 oncology & carcinogenesis Mad2 Proteins PARP inhibitor RNA Interference Tumor Suppressor p53-Binding Protein 1 DNA repair Ubiquitin-Protein Ligases Poly ADP ribose polymerase Telomere-Binding Proteins Ubiquitin-Protein Ligases/antagonists & inhibitors Mad2 Proteins/antagonists & inhibitors Biology Poly(ADP-ribose) Polymerase Inhibitors BRCA1 Protein/antagonists & inhibitors General Biochemistry Genetics and Molecular Biology Article Trans-Activators/genetics 03 medical and health sciences Cell Line Tumor Humans Adaptor Proteins Signal Transducing Immunoglobulin Class Switching Telomere MDC1 Nuclear Proteins/genetics 030104 developmental biology Tumor Suppressor p53-Binding Protein 1/antagonists & inhibitors chemistry Trans-Activators Mutagenesis Site-Directed Immunoglobulin Class Switching/drug effects DNA |
| Zdroj: | Gupta, R, Somyajit, K, Narita, T, Maskey, E, Stanlie, A, Kremer, M, Typas, D, Lammers, M, Mailand, N, Nussenzweig, A, Lukas, J & Choudhary, C 2018, ' DNA repair network analysis reveals shielding as a key regulator of NEHJ and PARP inhibitor sensitivity ', Cell, vol. 173, no. 4, pp. 972-988.e23 . https://doi.org/10.1016/j.cell.2018.03.050 Cell Gupta, R, Somyajit, K, Narita, T, Maskey, E, Stanlie, A, Kremer, M, Typas, D, Lammers, M, Mailand, N, Nussenzweig, A, Lukas, J & Choudhary, C 2018, ' DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity ', Cell, vol. 173, no. 4, pp. 972-988 . https://doi.org/10.1016/j.cell.2018.03.050 |
| DOI: | 10.1016/j.cell.2018.03.050 |
| Popis: | Repair of damaged DNA is essential for maintaining genome integrity and for preventing genome-instability-associated diseases, such as cancer. By combining proximity labeling with quantitative mass spectrometry, we generated high-resolution interaction neighborhood maps of the endogenously expressed DNA repair factors 53BP1, BRCA1, and MDC1. Our spatially resolved interaction maps reveal rich network intricacies, identify shared and bait-specific interaction modules, and implicate previously concealed regulators in this process. We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins, RINN1 (CTC-534A2.2), RINN2 (FAM35A), and RINN3 (C20ORF196). Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis, promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres. Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection and in sensitizing BRCA1-deficient cells to PARP inhibitors. These findings have implications for understanding cancer-associated PARPi resistance and the evolution of antibody CSR in higher vertebrates. Application of proximity-based quantitative proteomics allows the characterization of endogenous protein networks among major DNA damage repair factors and reveals the role of the protein complex shieldin in regulating NHEJ, antibody class switching, and sensitivity to PARP inhibitors. |
| Databáze: | OpenAIRE |
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