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MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer
Natsumi Tsuboyama1,2, Aileen Patricia Szczepanski1,2, Zibo Zhao1,2
1Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Genome Biology
|September 30, 2022
Summary
Methyl-CpG-binding domain proteins 5 and 6 (MBD5/MBD6) stabilize the BRCA1-associated protein 1 (BAP1) complex. MBD6 depletion reduces BAP1 chromatin occupancy, impacting gene expression and tumor growth in BAP1-dependent cancers.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Biology
Background:
- BRCA1-associated protein 1 (BAP1) is an epigenetic regulator involved in transcriptional activation.
- BAP1 forms a complex with epigenetic factors like ASXL1-3, but subunit interactions and functional impacts are unclear.
Purpose of the Study:
- Identify novel regulators of the BAP1 complex.
- Investigate the role of MBD5 and MBD6 in BAP1 complex stability and function.
- Explore therapeutic potential in BAP1-dependent cancers.
Main Methods:
- Protein complex identification and characterization.
- Ortholog identification in Drosophila (six-banded/SBA).
- Depletion studies (MBD6) in cancer cell lines and in vivo models.
Main Results:
- MBD5 and MBD6 bind to ASXL1-3, stabilizing the BAP1 complex at chromatin.
- The core BAP1 complex is conserved across species (Drosophila to human).
- MBD6 depletion causes global loss of BAP1 chromatin occupancy, reducing gene expression and tumor growth.
Conclusions:
- MBD5 and MBD6 are key regulators of the BAP1 complex.
- Targeting MBD5 and MBD6 offers therapeutic potential for BAP1-dependent cancers.
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