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.The mechanism of gene regulation by the H2A deubiquitinase BAP1 is unclear. Results BAP1 loss increases FoxK2 target gene expression but not in the absence of the H2A ubiquitin ligase complex Ring1B-Bmi1. Conclusion BAP1 counteracts Ring1B-Bmi1-dependent activation of FoxK2 target genes. Significance BAP1 deficiency in cancer cells might cause up-regulation of target genes in a Ring1B-Bmi1-dependent manner.