YY1 as a regulator of posttranslational modifications

YY1 was first identified as a transcription factor and has been shown to regulate the expression of many genes. However, our understanding of YY1 function has evolved with an increasing appreciation for its DNA-binding independent activities, many of which contribute to YYl-mediated gene expression.

Proteins undergo different types of post-translational modifications, including acetylation, methylation, ubiquitination and sumoylation that contribute to the complexity of protein stability, function and interactions. Many YYl-interaction partners mediate YYl-regulated gene expression through instigating post-translational modifications.

3.1. Acetylation

Acetylation is the addition of an acetyl group (CH3CO) to a lysine residue and mediated by a class of proteins called histone acetyltransferases (HATs). These enzymes catalyze acetyla-tion of both histone and non-histone proteins, and for this reason are more commonly referred to as lysine acetyltransferases (KATs) [73]. Acetylation of non-histone proteins modulates their activity and stablity, while histone acetylation is associated with a relatively loose or open chromatin conformation that is more accessible to transcriptional regulatory proteins, leading to active gene expression.

As we discussed above, YY1 interacts with the KAT p300 and this complex is disrupted in the presence of the viral protein E1A. Notably, YY1 and E1A bind to different domains of p300, and the binding sites of p300 and E1A on YY1 are also well separate [74]. Thus, it is very likely that these three proteins form a ternary complex. Such a complex would promote histone acetylation on promoters, such as P5, c-myc and c-Fos. This explains the role of E1A in converting YY1 from a transcriptional repressor to an activator to promote the expression of these target genes [2, 41, 75].

Acetylation of p53 by p300 both prevents its ubiquitination and subsequent degradation and enhances the p53-DNA interaction, thus promoting p53 transcriptional activity [76, 77]. YY1 inhibits p300-mediated p53 acetylation, thereby antagonizing the tumor suppressive function of p53 [47].

While histone acetylation is associated with active gene expression, histone deacetylation is a mark of gene repression and mediated by a family of proteins called histone deacetylases (HDACs). YY1 has been demonstrated to interact with a number of HDACs and recruit them to target promoters for gene repression. Indeed, YY1 recruitment of HDACs to tumor suppressor gene promoters is important for its role in prostate cancer, and will be discussed below.

3.2. Methylation

Like other modifications, methylation also modulates protein function. In this regard, the most studied activity is the contribution of histone methylation to gene expression. Al though DNA methylation usually inhibits gene expression, histone methylation can either activate or repress a target gene, depending on the methylated residues.

Protein arginine methyltransferase (PRMT) 1 catalyzes methylation of histone H4 at arginine 3 (H4-R3). YY1 recruits PRMT1 to the c-myc promoter to activate c-myc gene expression [9]. Similarly, YY1 has also been shown to activate the promoter of a pro-survival chaperone protein, GRP78, through recruiting PRMT1 [22]. YY1-mediated expression of these cell sur-ival genes suggests its proliferative role in oncogenesis.

The proteins enhancer of zeste (Ezh) 1 and 2 are lysine-specific histone methyltransferases mediating methylation of lysine 27 on histone 3 (H3-K27), a hallmark of gene silencing in many cancer-related genes [78]. They are both members of the Polycomb group (PcG) of proteins and core components of the Polycomb repressive complex (PRC) 2, responsible for gene silencing in a number of tumor suppressor genes.

YY1 was first demonstrated to recruit Ezh2 in mouse skeletal muscle cells [4]. The Recruitment of Polycomb (REPO) domain of YY1 is both necessary and sufficient to recruit Ezh2 and other PcG proteins for the establishment of target gene silencing [79].

In addition to histone methylation, YY1 can also mediate DNA methylation. This multi-layered regulation by YY1 has been demonstrated on the promoter of CCAAT/enhancer binding protein delta (CEBPD). YY1 associates with both DNA methyltransferases and PcG proteins to execute gene silencing through modifications of both DNA and histones [80].

3.3. Ubiquitination

Ubiquitination is a modification executed cooperatively by a set of three ubiquitin enzymes (E1, E2, and E3). Protein monoubiquitination typically alters subcellular localization of a protein or modulates its function and additional types of modification, while polyubiquiti-nation usually results in its proteasomal degradation.

In addition to the negative regulatory effects of YY1 on p53 discussed above, YY1 also promotes p53 polyubiquitination and degradation [47, 48]. YY1 directly interacts with both p53 and its E3 ligase Mdm2 and enhances the p53-Mdm2 interaction through the formation of a ternary complex. Both wild-type YY1 and its DNA-binding deficient mutant promote p53 polyubiquitination, indicating that this function of YY1 is independent of its transcriptional activity [48]. Consistently, YY1 depletion in cells leads to an increase in p53 stability and results in cell cycle arrest and apoptosis.

We recently identified negative regulation of the tumor suppressor p27 by YY1 through YY1-promoted ubiquitination [81]. YY1 overexpression enhanced both mono- and polyubi-quitination of p27, while YY1 silencing markedly reduced p27 polyubiquitination, but not monoubiquitination.

In summary, the large number of YY1's interaction partners increases the complexity of its biological functions. Many of these proteins (e.g. p300, PRMT1, Ezh2, etc.) contribute to YY1-mediated gene expression and modulate its Yin Yang effects on target genes. This transcriptional modulation is typically executed through YY1-recruited complexes initiating the addition or removal of different modifying groups on histone proteins. Other YY1-binding proteins contribute to the transcription-independent functions of YY1, such as Mdm2-medi-ated p53 ubiquitination and degradation.

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