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

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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02757608
Contributor : Chloé Lescale <>
Submitted on : Thursday, June 4, 2020 - 12:47:37 AM
Last modification on : Thursday, June 4, 2020 - 1:37:17 PM

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Harveer Dev, Ting-Wei Will Chiang, Chloé Lescale, Inge de Krijger, Alistair Martin, et al.. Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nature Cell Biology, Nature Publishing Group, 2018, 20 (8), pp.954-965. ⟨10.1038/s41556-018-0140-1⟩. ⟨pasteur-02757608⟩

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