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Dev, Harveer; Chiang, Ting-Wei Will; Lescale, Chloe; de Krijger, Inge; Martin, Alistair G; Pilger, Domenic; Coates, Julia; Sczaniecka-Clift, Matylda; Wei, Wenming; Ostermaier, Matthias; Herzog, Mareike; Lam, Jonathan; Shea, Abigail; Demir, Mukerrem; Wu, Qian; Yang, Fengtang; Fu, Beiyuan; Lai, Zhongwu; Balmus, Gabriel; Belotserkovskaya, Rimma; Serra, Violeta; O'Connor, Mark J; Bruna, Alejandra; Beli, Petra; Pellegrini, Luca; Caldas, Carlos; Deriano, Ludovic; Jacobs, Jacqueline J L; Galanty, Yaron; Jackson, Stephen P
Nature cell biology, 08/2018, Letnik: 20, Številka: 8Journal Article
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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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