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

Yuki Okino, Yuka Machida, Sarah Frankland-Searby, Yuichi Machida

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 BAP1DUBactivity 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.

Original languageEnglish (US)
Pages (from-to)1580-1591
Number of pages12
JournalJournal of Biological Chemistry
Volume290
Issue number3
DOIs
StatePublished - Jan 16 2015

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BRCA1 Protein
Ubiquitin
Genes
Chemical activation
Proteins
Histones
Deubiquitinating Enzymes
Gene Expression
Protein Deficiency
Ubiquitin-Protein Ligases
Gene expression

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the ubiquitin-mediated activation of FoxK2 target genes. / Okino, Yuki; Machida, Yuka; Frankland-Searby, Sarah; Machida, Yuichi.

In: Journal of Biological Chemistry, Vol. 290, No. 3, 16.01.2015, p. 1580-1591.

Research output: Contribution to journalArticle

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