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. 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

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

Rajat Gupta et al. Cell. .
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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.

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

Comment in

  • Shieldin the ends for 53BP1.
    Zlotorynski E. Zlotorynski E. Nat Rev Mol Cell Biol. 2018 Jun;19(6):346-347. doi: 10.1038/s41580-018-0019-9. Nat Rev Mol Cell Biol. 2018. PMID: 29700393 No abstract available.

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