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Cell. 2018 May 3;173(4):972-988.e23. doi: 10.1016/j.cell.2018.03.050. Epub 2018 Apr 12.

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

Author information

1
Proteomics Program, the Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
2
Protein Signaling Program, the Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
3
Laboratory of Genome Integrity, NIH, Bethesda, MD 20892, USA.
4
Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Joseph-Stelzmann-Str. 26, University of Cologne, 50931 Cologne, Germany.
5
Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Joseph-Stelzmann-Str. 26, University of Cologne, 50931 Cologne, Germany; Institute for Biochemistry, Synthetic and Structural Biochemistry, Felix-Hausdorff-Str. 4, University of Greifswald, 17487 Greifswald, Germany.
6
Proteomics Program, the Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark; Center for Chromosome Stability (CCS), Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark. Electronic address: chuna.choudhary@cpr.ku.dk.

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.

KEYWORDS:

53BP1; BRCA1; DNA damage repair; NHEJ; PARP inhibitors; antibody class-switch recombination; proteomics; proximity labeling; shieldin; telomere maintenance

PMID:
29656893
DOI:
10.1016/j.cell.2018.03.050
[Indexed for MEDLINE]

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