PXD043904 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC |
Description | The FBXW7 tumour suppressor is commonly mutated, deleted or hypermethylated in a variety of cancer histologies. The tumour suppressive role of the FBXW7 protein has been ascribed to its ability to drive the ubiquitination and degradation of oncoproteins via its role as a substrate recognition subunit of SCF complexes that mediate E3 ubiquitin ligation. Despite this molecular understanding, therapeutic approaches that target tumoural FBXW7 defects do not exist. To identify candidate vulnerabilities put in place by FBXW7 dysfunction, we carried out genome-wide CRISPR-Cas9 screens, focussed RNA interference screens and whole proteome mass spectrometry profiling in multiple FBXW7 wild type and defective isogenic cell systems. These identified candidate FBXW7 synthetic lethal effects, including those involving SCF-related proteins (e.g. CAND1), proteins involved in the response to replication fork stress (ATR, RAD9A and CHEK1) and also proteins involved in replication licencing such as CDC7 and its substrate GINS4. The ATR, CHEK1 and CDC7 synthetic lethal effects were confirmed using drug-like small molecule inhibitors. Integration of proteomic profiling data indicated that FBXW7 defective cells express elevated levels of the replication factor RIF1. Functional experiments showed that FBXW7 vs. CDC7 synthetic lethality is RIF1 dependent and explained by RIF1 being required for CDC7 inhibitor-induced replication fork stalling. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area. |
HostingRepository | PRIDE |
AnnounceDate | 2024-06-16 |
AnnouncementXML | Submission_2024-06-16_04:05:37.184.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Graeme Benstead-Hume |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2023-07-19 05:14:35 | ID requested | |
⏵ 1 | 2024-06-16 04:05:38 | announced | |
Publication List
Baxter JS, Brough R, Krastev DB, Song F, Sridhar S, Gulati A, Alexander J, Roumeliotis TI, Kozik Z, Choudhary JS, Haider S, Pettitt SJ, Tutt ANJ, Lord CJ, Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7. Mol Oncol, 18(2):369-385(2024) [pubmed] |
10.1002/1878-0261.13537; |
Keyword List
submitter keyword: CDC,FBXW7, synthetic lethal |
Contact List
Jyoti Choudhary |
contact affiliation | Functional Proteomics, ICR |
contact email | jyoti.choudhary@icr.ac.uk |
lab head | |
Graeme Benstead-Hume |
contact affiliation | ICR |
contact email | ghume@icr.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD043904
- Label: PRIDE project
- Name: Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC