Journal
NATURE CELL BIOLOGY
Volume 20, Issue 8, Pages 954-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-018-0140-1
Keywords
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Categories
Funding
- Cancer Research UK (CRUK) Program Grant [C6/A18796]
- Wellcome Trust (WT) Investigator Award [206388/Z/17/Z]
- CRUK [C6946/A24843]
- WT [WT203144, 104641/Z/14/Z]
- University of Cambridge
- WT Clinical Fellowship [206721/Z/17/Z]
- Cambridge International Scholarship
- Cancer Research UK studentship [C6/A21454]
- Emmy Noether Program from the German Research Foundation [BE 5342/1-1]
- Marie Curie Career Integration Grant from the European Commission [630763]
- Medical Research Council [MR/N000161/1]
- CRUK
- European Research Council [ERC-StG 311565, 310917]
- Dutch Cancer Society (KWF) [KWF 10999]
- Netherlands Organization for Scientific Research (NWO) as part of the National Roadmap Largescale Research Facilities of the Netherlands, Proteins@Work [184.032.201]
- Institut Pasteur
- Institut National du Cancer [PLBIO16-181]
- CNBG company, China
- Wellcome Trust [200814/Z/16/Z]
- Instituto de Salud Carlos III (ISCIII), an initiative of the Spanish Ministry of Economy and Innovation - European Regional Development FEDER Funds [PI17-01080]
- European Research Area-NET, Transcan-2 [AC15/00063]
- AstraZeneca UK
- Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) [2017 SGR 540]
- Orozco Family
- ISCIII [CP14/00228, MV15/00041]
- FERO Foundation
- European Research Council (ERC) [310917] Funding Source: European Research Council (ERC)
- Wellcome Trust [104641/Z/14/Z, 206721/Z/17/Z] Funding Source: Wellcome Trust
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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, C2Oorf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C2Oorf196 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.
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