PXD046273 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | A quality control factor for chromatin complexes is synthetic lethal in SMARCB1-mutant cancers |
Description | While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and is problematic because the tumor suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. Here, we report that the little-studied gene DDB1-CUL4 Associated Factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and promotes degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. Upon depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore SWI/SNF-mediated gene expression to levels sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality control factors may effectively reverse the malignant state of some cancers driven by disruption of tumor suppressor complexes. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_06:24:14.926.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Eric Fischer |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2023-10-20 16:23:21 | ID requested | |
1 | 2024-01-21 09:00:23 | announced | |
⏵ 2 | 2024-10-22 06:24:15 | announced | 2024-10-22: Updated project metadata. |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: Ubiquitin, cancer, DCAF5, SWI/SNF, protein degradation, SMARCB1, E3 ligase, chromatin |
Contact List
Eric Fischer |
contact affiliation | Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA |
contact email | eric_fischer@dfci.harvard.edu |
lab head | |
Eric Fischer |
contact affiliation | Dana-Farber Cancer Institute |
contact email | eric_fischer@dfci.harvard.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD046273
- Label: PRIDE project
- Name: A quality control factor for chromatin complexes is synthetic lethal in SMARCB1-mutant cancers