Universität zu Köln

Gupta, Rajat, Somyajit, Kumar ORCID: 0000-0003-2496-7155, Narita, Takeo ORCID: 0000-0002-2705-7838, Maskey, Elina, Stanlie, Andre, Kremer, Magdalena, Typas, Dimitris ORCID: 0000-0002-8737-1319, Lammers, Michael ORCID: 0000-0003-4168-4640, Mailand, Niels, Nussenzweig, Andre, Lukas, Jiri and Choudhary, Chunaram (2018). DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell, 173 (4). S. 972 - 1012. CAMBRIDGE: CELL PRESS. ISSN 1097-4172

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gupta, Rajat UNSPECIFIED UNSPECIFIED UNSPECIFIED Somyajit, Kumar UNSPECIFIED orcid.org/0000-0003-2496-7155 UNSPECIFIED Narita, Takeo UNSPECIFIED orcid.org/0000-0002-2705-7838 UNSPECIFIED Maskey, Elina UNSPECIFIED UNSPECIFIED UNSPECIFIED Stanlie, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Kremer, Magdalena UNSPECIFIED UNSPECIFIED UNSPECIFIED Typas, Dimitris UNSPECIFIED orcid.org/0000-0002-8737-1319 UNSPECIFIED Lammers, Michael UNSPECIFIED orcid.org/0000-0003-4168-4640 UNSPECIFIED Mailand, Niels UNSPECIFIED UNSPECIFIED UNSPECIFIED Nussenzweig, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Lukas, Jiri UNSPECIFIED UNSPECIFIED UNSPECIFIED Choudhary, Chunaram UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-186675
DOI:	10.1016/j.cell.2018.03.050
Journal or Publication Title:	Cell
Volume:	173
Number:	4
Page Range:	S. 972 - 1012
Date:	2018
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1097-4172
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DAMAGE-RESPONSE; 53BP1; BRCA1; CELLS; RESECTION; SWITCH; REPLICATION; ANNOTATION; TELOMERES; PATHWAYS Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18667