DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity
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DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. / Gupta, Rajat; Somyajit, Kumar; Narita, Takeo; Maskey, Elina; Stanlie, Andre; Kremer, Magdalena; Typas, Dimitris; Lammers, Michael; Mailand, Niels; Nussenzweig, Andre; Lukas, Jiri; Choudhary, Chunaram.
In: Cell, Vol. 173, No. 4, 2018, p. 972-988.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity
AU - Gupta, Rajat
AU - Somyajit, Kumar
AU - Narita, Takeo
AU - Maskey, Elina
AU - Stanlie, Andre
AU - Kremer, Magdalena
AU - Typas, Dimitris
AU - Lammers, Michael
AU - Mailand, Niels
AU - Nussenzweig, Andre
AU - Lukas, Jiri
AU - Choudhary, Chunaram
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1016/j.cell.2018.03.050
DO - 10.1016/j.cell.2018.03.050
M3 - Journal article
C2 - 29656893
VL - 173
SP - 972
EP - 988
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
ER -
ID: 195258552