PXD039706

PXD039706 is an original dataset announced via ProteomeXchange.

Title	BRWD3 targets KDM5/Lid for degradation to maintain H3K4 methylation levels
Description	Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modification levels may contribute to disease development and cancer. Therefore, understanding histone modifications is essential for development and disease. The chromatin-binding protein BRWD3, a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, is required for maintaining active histone modification levels. Loss of BRWD3 function causes an increase in H3K4me1 levels. The underline mechanism, however, is unknown. We found that BRWD3 depletion also causes a decrease in H3K4me3 levels. To reveal the mechanism by which BRWD3 regulates the H3K4 methylation levels, we performed BRWD3-IP mass-spectrometry. We identified an interaction between BRWD3 and the lysine-specific demethylase 5 (KDM5/Lid), an enzyme that removes tri- and di- methyl marks from lysine 4 on histone H3. Moreover, analysis of ChIP-seq data revealed that BRWD3 and KDM5 are significantly co-localized throughout the genome. We show that BRWD3 promotes K48-linked ubiquitination of KDM5. Consistent with this, KDM5/Lid is rapidly degraded in a proteasome-dependent manner with a half-life of less than 30 mins. Critically, KDM5/Lid degradation is dependent on both BRWD3 and Cul4. In addition, we have found that BRWD3 is suppressor of Position-effect variegation (PEV). Loss of a single copy of KDM5, however, partially rescues the the BRWD3 PEV phenotype. Our results suggest that BRWD3 targets KDM5/Lid for degradation to ensure the balance of H3K4me levels.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:05:21.258.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jonathan Davies
SpeciesList	scientific name: Drosophila melanogaster (Fruit fly); NCBI TaxID: 7227;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-01-27 10:50:22	ID requested
1	2023-09-19 15:19:12	announced
⏵ 2	2023-11-14 09:05:24	announced	2023-11-14: Updated project metadata.

Han D, Schaffner SH, Davies JP, Benton ML, Plate L, Nordman JT, BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels. Proc Natl Acad Sci U S A, 120(39):e2305092120(2023) [pubmed]

submitter keyword: H3K4, histone, degradation, E3 ubiquitin ligase,BRWD3

Jared Nordman
contact affiliation	Department of Biological Sciences, Vanderbilt University
contact email	jared.nordman@vanderbilt.edu
lab head
Jonathan Davies
contact affiliation	Vanderbilt University
contact email	jonathan.p.davies@vanderbilt.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD039706
     1. Label: PRIDE project
     2. Name: BRWD3 targets KDM5/Lid for degradation to maintain H3K4 methylation levels