dc.contributor.author | Dev, H | |
dc.contributor.author | Chiang, T-WW | |
dc.contributor.author | Lescale, C | |
dc.contributor.author | de Krijger, I | |
dc.contributor.author | Martin, AG | |
dc.contributor.author | Pilger, D | |
dc.contributor.author | Coates, J | |
dc.contributor.author | Sczaniecka-Clift, M | |
dc.contributor.author | Wei, W | |
dc.contributor.author | Ostermaier, M | |
dc.contributor.author | Herzog, M | |
dc.contributor.author | Lam, J | |
dc.contributor.author | Shea, A | |
dc.contributor.author | Demir, M | |
dc.contributor.author | Wu, Q | |
dc.contributor.author | Yang, F | |
dc.contributor.author | Fu, B | |
dc.contributor.author | Lai, Z | |
dc.contributor.author | Balmus, G | |
dc.contributor.author | Belotserkovskaya, R | |
dc.contributor.author | Serra, V | |
dc.contributor.author | O'Connor, MJ | |
dc.contributor.author | Bruna, A | |
dc.contributor.author | Beli, P | |
dc.contributor.author | Pellegrini, L | |
dc.contributor.author | Caldas, C | |
dc.contributor.author | Deriano, L | |
dc.contributor.author | Jacobs, JJL | |
dc.contributor.author | Galanty, Y | |
dc.contributor.author | Jackson, SP | |
dc.date.accessioned | 2020-08-05T10:56:46Z | |
dc.date.issued | 2018-08-01 | |
dc.identifier.citation | Nature cell biology, 2018, 20 (8), pp. 954 - 965 | |
dc.identifier.issn | 1465-7392 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3901 | |
dc.identifier.eissn | 1476-4679 | |
dc.identifier.doi | 10.1038/s41556-018-0140-1 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 954 - 965 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Osteosarcoma | |
dc.subject | Bone Neoplasms | |
dc.subject | Breast Neoplasms | |
dc.subject | Ovarian Neoplasms | |
dc.subject | Cisplatin | |
dc.subject | Multiprotein Complexes | |
dc.subject | Proteins | |
dc.subject | Cell Cycle Proteins | |
dc.subject | DNA-Binding Proteins | |
dc.subject | Telomere-Binding Proteins | |
dc.subject | BRCA1 Protein | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Female | |
dc.subject | DNA Breaks, Double-Stranded | |
dc.subject | HEK293 Cells | |
dc.subject | DNA End-Joining Repair | |
dc.subject | Recombinational DNA Repair | |
dc.subject | Mad2 Proteins | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | Tumor Suppressor p53-Binding Protein 1 | |
dc.title | Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-06-11 | |
rioxxterms.versionofrecord | 10.1038/s41556-018-0140-1 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2018-08 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature cell biology | |
pubs.issue | 8 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Preclinical Modelling of Paediatric Cancer Evolution | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Preclinical Modelling of Paediatric Cancer Evolution | |
pubs.publication-status | Published | |
pubs.volume | 20 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Preclinical Modelling of Paediatric Cancer Evolution | |
dc.contributor.icrauthor | Bruna Cabot, Alejandra | |