BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the ubiquitin-mediated activation of FoxK2 target genes.
J Biol Chem
; 290(3): 1580-91, 2015 Jan 16.
Article
em En
| MEDLINE
| ID: mdl-25451922
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação Enzimológica da Expressão Gênica
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Proteínas Supressoras de Tumor
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Ubiquitina
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Ubiquitina Tiolesterase
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Fatores de Transcrição Forkhead
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Complexo Repressor Polycomb 1
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2015
Tipo de documento:
Article