BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the ubiquitin-mediated activation of FoxK2 target genes.

BRCA1-associated protein 1 (BAP1), which is frequently mutated in cancer, functions as a deubiquitinase (DUB) for histone H2A. Although BAP1 interacts with a transcriptional regulator, HCF-1, and transcription factors FoxK1 and FoxK2, how BAP1 controls gene expression remains unclear. This study investigates the importance of BAP1 DUB activity and the ...
interactions with FoxK2 and HCF-1 in the regulation of FoxK2 target genes. We show that FoxK2 recruits BAP1 to the target genes through the forkhead-associated domain, which interacts with Thr(P)-493 on BAP1. BAP1, in turn, recruits HCF-1, thereby forming a ternary complex in which BAP1 bridges FoxK2 and HCF-1. BAP1 represses FoxK2 target genes, and this effect requires BAP1 DUB activity but not interaction with HCF-1. Importantly, BAP1 depletion causes up-regulation of FoxK2 target genes only in the presence of the Ring1B-Bmi1 complex, an E3 ubiquitin ligase for histone H2A, indicating an antagonizing role of BAP1 against Ring1B-Bmi1. Our findings suggest that BAP1 deficiency causes increased expression of target genes in a Ring1B-Bmi1-dependent manner.
Mesh Terms:
Amino Acid Sequence, Chromatin, Forkhead Transcription Factors, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Glutathione Transferase, HEK293 Cells, Humans, Molecular Sequence Data, Neoplasms, Phosphorylation, Polycomb Repressive Complex 1, Protein Binding, Protein Structure, Tertiary, RNA Interference, Recombinant Proteins, Sequence Homology, Amino Acid, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin Thiolesterase, Up-Regulation
J. Biol. Chem.
Date: Jan. 16, 2015
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