title: BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the ubiquitin-mediated activation of FoxK2 target genes.
abstract: 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.
authors.affiliation: From the Departments of Oncology and.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okino
authors.affiliation: From the Departments of Oncology and.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Machida
authors.affiliation: Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Sarah
authors.initials: S
authors.lastname: Frankland-Searby
authors.affiliation: From the Departments of Oncology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905 machida.yuichi@mayo.edu.
authors.forename: Yuichi J
authors.initials: YJ
authors.lastname: Machida
mesh_terms: D000595:Amino Acid Sequence; D002843:Chromatin / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C400134:BAP1 protein, human; C069077:BMI1 protein, human; D002843:Chromatin; D051858:Forkhead Transcription Factors; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C070635:interleukin binding factor; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human; D005982:Glutathione Transferase; D043222:Ubiquitin Thiolesterase
keywords: Deubiquitylation (Deubiquitination); Gene Expression; Phosphorylation; Tumor Suppressor Gene; Ubiquitin