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Series GSE196860 Query DataSets for GSE196860
Status Public on Sep 15, 2022
Title MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary The BRCA1-associated protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase (UCH), which forms a multi-protein complex with different epigenetic factors such as ASXL1-3, and FOXK1/2. At chromatin, BAP1 catalyzes the removal of mono-ubiquitination on histone H2AK119 in collaboration with other subunits within the complex, and therefore functions as a transcriptional activator. However, the crosstalk between different subunits and how these subunits impact BAP1 function remains unclear. Here, we report the identification of the methyl-CpG-binding domain proteins 5 and 6 (MBD5 and MBD6) that bind to the C-terminal PHD fingers of the large scaffold subunits ASXL1-3 and stabilize the BAP1 complex at chromatin. We further identified a previously uncharacterized Drosophila protein, the six-banded (SBA), as the ortholog of human MBD5/6. We demonstrated the core module of the BAP1 complex is structurally and functionally conserved during the evolution from Drosophila (Calypso/ASX/SBA) to human cells (BAP1/ASXL/MBD). Dysfunction of the BAP1 complex induced by the misregulation/mutations in each subunit is frequent in human cancer. In BAP1-dependent human cancers, MBD6 tends to be a dominant form. Depletion of MBD6 leads to a global loss of BAP1 occupancy at chromatin, resulting in a reduction of BAP1-dependent gene expression and tumor growth in vitro and in vivo. In summary, our study has uncovered MBD5/6 as important regulators of the BAP1 complex and transcription, and sheds light on the therapeutic potential of targeting MBD5/6 in human cancer.
Overall design This study aims to provide mechanistic insight into the function of MBD5/6 in BAP1 complex .
Contributor(s) Zhao Z, Wang L
Citation(s) 36180891
Submission date Feb 16, 2022
Last update date Oct 05, 2022
Contact name Lu Wang
Organization name Northwestern University
Department Biochemistry and Molecular Genetics
Lab Lu Wang
Street address 303 E. Superior Street Simpson Querrey 7-414
City Chicago
State/province Illinois
ZIP/Postal code 60611
Country USA
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (72)
GSM5903228 H1963_BAP1
GSM5903229 H1963_ASXL1
GSM5903230 H1963_ASXL2
BioProject PRJNA807606

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Supplementary file Size Download File type/resource
GSE196860_RAW.tar 14.2 Gb (http)(custom) TAR (of BW)
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Raw data are available in SRA
Processed data provided as supplementary file

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