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

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Date
2018-08
ICR Author
Bruna Cabot, Alejandra
Author
Dev, H
Chiang, T-WW
Lescale, C
de Krijger, I
Martin, AG
Pilger, D
Coates, J
Sczaniecka-Clift, M
Wei, W
Ostermaier, M
Herzog, M
Lam, J
Shea, A
Demir, M
Wu, Q
Yang, F
Fu, B
Lai, Z
Balmus, G
Belotserkovskaya, R
Serra, V
O'Connor, MJ
Bruna, A
Beli, P
Pellegrini, L
Caldas, C
Deriano, L
Jacobs, JJL
Galanty, Y
Jackson, SP
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/3901
DOI
https://doi.org/10.1038/s41556-018-0140-1
Collections
  • Molecular Pathology
Subject
Cell Line, Tumor
Animals
Humans
Mice
Osteosarcoma
Bone Neoplasms
Breast Neoplasms
Ovarian Neoplasms
Cisplatin
Multiprotein Complexes
Proteins
Cell Cycle Proteins
DNA-Binding Proteins
Telomere-Binding Proteins
BRCA1 Protein
Xenograft Model Antitumor Assays
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Female
DNA Breaks, Double-Stranded
HEK293 Cells
DNA End-Joining Repair
Recombinational DNA Repair
Mad2 Proteins
Poly(ADP-ribose) Polymerase Inhibitors
Tumor Suppressor p53-Binding Protein 1
Research team
Preclinical Modelling of Paediatric Cancer Evolution
Language
eng
Date accepted
2018-06-11
License start date
2018-08
Citation
Nature cell biology, 2018, 20 (8), pp. 954 - 965

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