PXD043904

PXD043904 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-19 05:14:35	ID requested
⏵ 1	2024-06-16 04:05:38	announced

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;

submitter keyword: CDC,FBXW7, synthetic lethal

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

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PRIDE project URI

• PRIDE
  1. PXD043904
     1. Label: PRIDE project
     2. Name: Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC