PXD009830-2
PXD009830 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | Shieldin complex promotes DNA end joining and counters homologous recombination in BRCA1-null cells |
Description | BRCA1 deficiencies cause breast, ovarian and other cancers, and render tumours hypersensitive to PARP-inhibitors. To understand resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP-inhibitors. Thus, 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, termed “Shieldin” (SHLD1/2), with FAM35A interacting with single-stranded DNA via its C-terminal OB-fold region. We establish that Shieldin promotes DNA double-strand break (DSB) end-joining, acting as the downstream effector of 53BP1/RIF1/MAD2L2 to restrict DSB resection and counteract homologous recombination in BRCA1-deficient cells by antagonising BRCA2/RAD51 loading. Notably, Shieldin inactivation further sensitises 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. |
HostingRepository | PRIDE |
AnnounceDate | 2018-05-31 |
AnnouncementXML | Submission_2019-06-14_07:41:57.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Petra Beli |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2018-05-18 04:25:22 | ID requested | |
1 | 2018-05-30 19:01:09 | announced | |
⏵ 2 | 2019-06-14 07:41:59 | announced | Updated publication reference for PubMed record(s): 30022119. |
Publication List
Dev H, Chiang TW, 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, Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat Cell Biol, 20(8):954-965(2018) [pubmed] |
Keyword List
curator keyword: Biological, Biomedical |
submitter keyword: C20orf196, FAM35A, Shieldin |
Contact List
Petra Beli | |
---|---|
contact affiliation | Institute of Molecular Biology (IMB), Mainz, Germany |
contact email | p.beli@imb-mainz.de |
lab head | |
Petra Beli | |
contact affiliation | Institute of Molecular Biology (IMB), Mainz, Germany |
contact email | p.beli@imb-mainz.de |
dataset submitter |
Full Dataset Link List
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PRIDE project URI |
Repository Record List
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