The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression.
The candidate tumor suppressor BAP1 is a deubiquitinating enzyme (DUB) involved in the regulation of cell proliferation, although the molecular mechanisms governing its function remain poorly defined. BAP1 was recently shown to interact with and deubiquitinate the transcriptional regulator host cell factor 1 (HCF-1). Here we show that BAP1 assembles multiprotein complexes containing numerous transcription factors and cofactors, including HCF-1 and the transcription factor Yin Yang 1 (YY1). Through its coiled-coil motif, BAP1 directly interacts with the zinc fingers of YY1. Moreover, HCF-1 interacts with the middle region of YY1 encompassing the glycine-lysine-rich domain and is essential for the formation of a ternary complex with YY1 and BAP1 in vivo. BAP1 activates transcription in an enzymatic-activity-dependent manner and regulates the expression of a variety of genes involved in numerous cellular processes. We further show that BAP1 and HCF-1 are recruited by YY1 to the promoter of the cox7c gene, which encodes a mitochondrial protein used here as a model of BAP1-activated gene expression. Our findings (i) establish a direct link between BAP1 and the transcriptional control of genes regulating cell growth and proliferation and (ii) shed light on a novel mechanism of transcription regulation involving ubiquitin signaling.
Yu
Helen
H
University of Montréal, Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, Montréal, Québec, Canada.
Mashtalir
Nazar
N
Daou
Salima
S
Hammond-Martel
Ian
I
Ross
Julie
J
Sui
Guangchao
G
Hart
Gerald W
GW
Rauscher
Frank J
FJ
Drobetsky
Elliot
E
Milot
Eric
E
Shi
Yang
Y
Affar
El Bachir
el B
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics; D006367:HeLa Cells; D051863:Host Cell Factor C1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D050986:YY1 Transcription Factor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D004247:DNA; D003576:Electron Transport Complex IV; D051863:Host Cell Factor C1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase; D050986:YY1 Transcription Factor; C400134:BAP1 protein, human; C105520:COX7C protein, human; C497692:HCFC1 protein, human; C494698:YY1 protein, human
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