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

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.
Mesh Terms:
BRCA1 Protein, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA-Binding Proteins, Humans, Immunoglobulin Class Switching, Mad2 Proteins, Mutagenesis, Site-Directed, Nuclear Proteins, Poly(ADP-ribose) Polymerase Inhibitors, RNA Interference, RNA, Small Interfering, Telomere-Binding Proteins, Trans-Activators, Tumor Suppressor p53-Binding Protein 1, Ubiquitin-Protein Ligases
Cell
Date: Dec. 03, 2017
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