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Nat Cell Biol. 2018 Aug;20(8):954-965. doi: 10.1038/s41556-018-0140-1. Epub 2018 Jul 18.

Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells.

Author information

1
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
2
Academic Urology Group, Department of Surgery, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK.
3
Genome Integrity, Immunity and Cancer Unit, Department of Immunology, Department of Genomes and Genetics, Institut Pasteur, Paris, France.
4
Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan , Amsterdam, the Netherlands.
5
Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
6
Institute of Molecular Biology (IMB), Mainz, Germany.
7
Department of Biochemistry, University of Cambridge, Cambridge, UK.
8
Wellcome Trust Sanger Institute, Hinxton, UK.
9
AstraZeneca, Waltham, MA, USA.
10
Vall d'Hebron Institute of Oncology, Barcelona, Spain.
11
AstraZeneca, Cambridge, UK.
12
Genome Integrity, Immunity and Cancer Unit, Department of Immunology, Department of Genomes and Genetics, Institut Pasteur, Paris, France. ludovic.deriano@pasteur.fr.
13
Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan , Amsterdam, the Netherlands. j.jacobs@nki.nl.
14
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK. y.galanty@gurdon.cam.ac.uk.
15
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK. s.jackson@gurdon.cam.ac.uk.

Abstract

BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance.

PMID:
30022119
PMCID:
PMC6145444
[Available on 2019-01-18]
DOI:
10.1038/s41556-018-0140-1

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