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| 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
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| 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.
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| Overall design |
This study aims to provide mechanistic insight into the function of MBD5/6 in BAP1 complex .
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| Contributor(s) |
Zhao Z, Wang L |
| Citation(s) |
36180891 |
| |
| Submission date |
Feb 16, 2022 |
| Last update date |
Oct 05, 2022 |
| Contact name |
Lu Wang |
| E-mail(s) |
lu.wang1@northwestern.edu
|
| Organization name |
Northwestern University
|
| Department |
Biochemistry and Molecular Genetics
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| Lab |
Lu Wang
|
| Street address |
303 E. Superior Street Simpson Querrey 7-414
|
| City |
Chicago |
| State/province |
Illinois |
| ZIP/Postal code |
60611 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (72)
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| Relations |
| BioProject |
PRJNA807606 |
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