PXD037497

PXD037497 is an original dataset announced via ProteomeXchange.

Title	Loss of the E3 ubiquitin ligases UBR-5 or HECD-1 restores Caenorhabditis elegans development in the absence of SWI/SNF function
Description	SWItch/Sucrose Non-Fermenting (SWI/SNF) complexes are a family of chromatin remodellers that are conserved across eukaryotes. Mutations in subunits of SWI/SNF cause a multitude of different developmental disorders in humans, most of which have no current treatment options. Here we identify an alanine to valine causing mutation in the SWI/SNF subunit snfc-5 (SMARCB1 in humans) that prevents embryonic lethality in C. elegans nematodes harbouring a loss-of-function mutation in the SWI/SNF subunit swsn-1 (SMARCC1/2 in humans). Furthermore, we found that the combination of this specific mutation in snfc-5 and a loss-of-function mutation in either of the E3 ubiquitin ligases ubr-5 (UBR5 in humans) or hecd-1 (HECTD1 in humans) can restore development to adulthood in swsn-1 loss-of-function mutants that otherwise die as embryos. Using these mutant models, we established a set of 335 genes that are dysregulated in SWI/SNF mutants that arrest their development embryonically but exhibit near wild-type levels of expression in the presence of suppressor mutations that prevent embryonic lethality, suggesting that SWI/SNF promotes development by regulating this specific subset of genes. In addition, we show that SWI/SNF protein levels are reduced in swsn-1; snfc-5 double mutants and partly restored to wild-type levels in swsn-1; snfc-5; ubr-5 triple mutants, consistent with a model in which UBR-5 regulates SWI/SNF levels by tagging the complex for proteasomal degradation. Our findings establish a link between two E3 ubiquitin ligases and SWI/SNF function and suggest that UBR5 and HECTD1 might be viable therapeutic targets for the many developmental disorders caused by missense mutations in SWI/SNF subunits.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:32:20.830.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Petra Beli
SpeciesList	scientific name: Caenorhabditis elegans; NCBI TaxID: 6239;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-17 01:38:52	ID requested
1	2023-01-24 15:42:19	announced
⏵ 2	2023-11-14 08:32:22	announced	2023-11-14: Updated project metadata.

Lampersberger L, Conte F, Ghosh S, Xiao Y, Price J, Jordan D, Matus DQ, Sarkies P, Beli P, Miska EA, Burton NO, development in the absence of SWI/SNF function. Proc Natl Acad Sci U S A, 120(5):e2217992120(2023) [pubmed]

submitter keyword: HECD-1, UBR-5, development,SWI/SNF, ubiquitination, UBR5, HECTD1, C. elegans

Petra Beli
contact affiliation	Institute of Molecular Biology gGmbH(IMB), Mainz, 55128, 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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/01/PXD037497

PRIDE project URI

• PRIDE
  1. PXD037497
     1. Label: PRIDE project
     2. Name: Loss of the E3 ubiquitin ligases UBR-5 or HECD-1 restores Caenorhabditis elegans development in the absence of SWI/SNF function