The Ubiquitin Carboxyl Hydrolase BAP1 Forms a Ternary Complex with YY1 and HCF-1 and Is a Critical Regulator of Gene Expression

Abstract

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.Posttranslational modification of proteins with ubiquitin plays a central role in a wide variety of biological processes in eukaryotic cells (44,64). Depending on the nature of the modification (e.g., poly-versus monoubiquitination), modified substrates can be either degraded by the proteasome or regulated at the level of their activity and function (4, 45). Ubiquitination is reversible, and a significant repertoire of proteases, termed deubiquitinating enzymes (DUBs), are emerging as critical regulators of ubiquitin signaling (40,46). BAP1 (BRCA1-associated protein 1) was originally isolated as a nuclear DUB that interacts with, and enhances the growthsuppressive effect of, the tumor suppressor BRCA1 (19). BAP1 also acts in a BRCA1-independent manner; its overexpression in cells lacking BRCA1 has been shown to inhibit cell proliferation and tumor growth (60). Interestingly, recent studies indicate that RNA interference (RNAi)-mediated depletion of BAP1 can also exert an inhibitory effect on cell proliferation (31,36,41). Although the exact molecular mechanisms are largely unknown, these data suggest that BAP1 controls cell cycle progression. In further support of this notion, homozygous inactivating mutations in BAP1 have been found in subsets of lung carcinoma and breast cancer cell lines, suggesting that this DUB is a tumor suppressor (19,67).

Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair

“…We emphasize that BAP1 heterozygous clones also exhibit chromosomal defects and decreased HR-mediated sIgM reversion. These observations suggest that BAP1 dosage is critical, which may reflect the fact that all nuclear BAP1 is contained within multiprotein complexes (13). Indeed, BAP1 heterozygous mutations are found in human tumors (29).…”

“…BAP1 forms multiprotein complexes with several chromatin-associated proteins, notably the host cell factor 1 (HCF-1), and regulates transcription (13). The Drosophila BAP1, Calypso, was shown to deubiquitinate H2Aub (14).…”

BRCA1-associated Protein 1 (BAP1) Deubiquitinase Antagonizes the Ubiquitin-mediated Activation of FoxK2 Target Genes

“…In fact, a study in human cells has shown that BAP1 activates YY1-regulated genes in a DUB-dependent manner (22). In addition, genome-wide gene expression analyses showed that many genes are up-or down-regulated by BAP1 knockdown or knockout, indicating that BAP1 can be a corepressor or coactivator (13,22,23 are needed to understand which genes are regulated by BAP1, how BAP1 is recruited to the target genes, and how BAP1 controls gene expression. In particular, assessing the role of DUB activity and the requirement of the interactions with coregulators such as HCF-1 are necessary to figure out the complex mechanism of gene regulation by BAP1.…”

HCF-1 self-association via an interdigitated Fn3 structure facilitates transcriptional regulatory complex formation

“…HCF-1 was initially identified as a human coactivator for immediate-early gene expression of herpes simplex virus (HSV) by forming a complex (VP16-induced complex, VIC) with the HSV protein VP16 and the cellular transcriptional regulator Oct-1 (1). HCF-1 regulates cell-cycle progression by mediating associations between DNA-binding transcription factors and chromatin modifying complexes (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”