DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

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 journalJournal articleResearchpeer-review

Harvard

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

APA

Gupta, R., Somyajit, K., Narita, T., Maskey, E., Stanlie, A., Kremer, M., ... Choudhary, C. (2018). DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell, 173(4), 972-988. https://doi.org/10.1016/j.cell.2018.03.050

Vancouver

Gupta R, Somyajit K, Narita T, Maskey E, Stanlie A, Kremer M et al. DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell. 2018;173(4):972-988. https://doi.org/10.1016/j.cell.2018.03.050

Author

Gupta, Rajat ; Somyajit, Kumar ; Narita, Takeo ; Maskey, Elina ; Stanlie, Andre ; Kremer, Magdalena ; Typas, Dimitris ; Lammers, Michael ; Mailand, Niels ; Nussenzweig, Andre ; Lukas, Jiri ; Choudhary, Chunaram. / DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. In: Cell. 2018 ; Vol. 173, No. 4. pp. 972-988.

Bibtex

@article{0b5b6081852a44778500e1e4597525f3,
title = "DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity",
abstract = "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.",
author = "Rajat Gupta and Kumar Somyajit and Takeo Narita and Elina Maskey and Andre Stanlie and Magdalena Kremer and Dimitris Typas and Michael Lammers and Niels Mailand and Andre Nussenzweig and Jiri Lukas and Chunaram Choudhary",
note = "Copyright {\circledC} 2018 Elsevier Inc. All rights reserved.",
year = "2018",
doi = "10.1016/j.cell.2018.03.050",
language = "English",
volume = "173",
pages = "972--988",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",

}

RIS

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

VL - 173

SP - 972

EP - 988

JO - Cell

JF - Cell

SN - 0092-8674

IS - 4

ER -

ID: 195258552