Disease relevance of CBX5

• In this study, we have engineered a modified embryonal carcinoma F9 cell line (TIF1beta(HP1box/-)) expressing a mutated TIF1beta protein (TIF1beta(HP1box)) unable to interact with HP1 proteins [1].
• Given the role of HP1 in transcriptional silencing in Drosophila, we propose a model in which HP1Hsalpha normally silences genes involved in breast cancer invasion and metastasis [2].
• The cooccurrence of autoantibodies to centromere proteins and HP1 in certain autoimmune diseases might be a reflection of coordinated immune responses to these closely associated sets of proteins [3].
• Human HP1 was expressed as a GST-fusion in Escherichia coli and purified with glutathione-Sepharose [4].
• Taken together, these data demonstrate that modulation of HP1(Hsalpha) alters the invasive potential of breast cancer cells through mechanisms requiring HP1 dimerization, but not interactions with PXVXL-containing proteins [5].

High impact information on CBX5

• Heterochromatin is characterized by the methylation of cytosine nucleotides of the DNA, the methylation of histone H3 at lysine 9 (H3 Lys 9), and the specific binding of heterochromatin protein 1 (HP1) to methylated H3 Lys 9 (refs 1-7) [6].
• In eukaryotic cells the histone methylase SUV39H1 and the methyl-lysine binding protein HP1 functionally interact to repress transcription at heterochromatic sites [7].
• Lysine 9 of histone H3 is methylated by SUV39H1 (ref. 2), creating a binding site for the chromo domain of HP1 (refs 3, 4) [7].
• Phosphorylation of H3S10 by Aurora B leads to dissociation of HP1 proteins from methylated H3K9 residues on mitotic heterochromatin [8].
• The HP1 proteins reassociate with chromatin at the end of mitosis, as histone H3 is dephosphorylated [9].

Biological context of CBX5

• These data indicate that MBD1 may tether the Suv39h1-HP1 complex to methylated DNA regions, suggesting the presence of a pathway from DNA methylation to the modifications of histones for epigenetic gene regulation [10].
• INCENP centromere and spindle targeting: identification of essential conserved motifs and involvement of heterochromatin protein HP1 [11].
• Heterochromatin protein 1 (HP1) plays an important role in heterochromatin formation and undergoes large-scale, progressive dissociation from heterochromatin in prophase cells [12].
• Our data define a molecular mechanism through which the SUV39H-HP1 methylation system can contribute to the propagation of heterochromatic subdomains in native chromatin [13].
• Methylation of histone H3 at lysine 9 by SUV39H1 and subsequent recruitment of the heterochromatin protein HP1 has recently been linked to gene silencing [14].

Anatomical context of CBX5

• The modular domain organization of HP1-type proteins and LBR can explain some of the diverse protein-protein interactions at the chromatin-lamina-membrane interface of the nuclear envelope [15].
• Collectively, these data demonstrate that the interaction between TIF1beta and HP1 proteins is essential for progression through differentiation by regulating the expression of endoderm differentiation master players [1].
• We have recently demonstrated that heterochromatin HP1 proteins are aberrantly distributed in lymphocytes of patients with immunodeficiency, centromeric instability and facial dysmorphy (ICF) syndrome [16].
• This interaction can be manipulated in living cells, as evidenced by ectopic expression of GFP-tagged HP1 proteins in HeLa cells, which results in a dramatic relocalization of endogenous pKi-67 [17].
• Proteins containing the conserved chromodomain motif that is common to the Polycomb-group (Pc-G) proteins and the heterochromatin-associated protein HP1, play essential roles in these processes and more specifically, in X-chromosome inactivation in female zygotes and extra-embryonic tissues and in the regulation of genomic imprinting [18].

Associations of CBX5 with chemical compounds

• Here we show that histone H3 methylase Suv39h1 and the methyl lysine-binding protein HP1 directly interact with MBD of MBD1 in vitro and in cells [10].
• Here, we characterized the inactive transgenic locus as heterochromatin, since it was associated with heterochromatin protein 1 (HP1), histone H3 trimethylated at lysine 9, and cytosine methylation in CpG dinucleotides [19].
• Here we show that cysteine substitution at Ala-395, Ala-367, and Ala-440 results in functional single and double cysteine transporters and that in the absence of glutamate or dl-threo-beta-benzyloxyaspartate (dl-TBOA), A395C in the highly conserved TM7 can be cross-linked to A367C in HP1 and to A440C in HP2 [20].
• Both modifications lead to the binding of specific proteins; bromodomain proteins, such as GCN5, bind acetyl lysines and the chromodomain protein, HP1, binds methyl lysine 9 of histone H3 [21].
• Recently, we and others presented evidence that a "binary methylation-phosphorylation switch" mechanism controls the dynamic release of HP1 from H3K9me3 during the cell cycle: phosphorylation of histone H3 serine 10 (H3S10ph) occurs at the onset of mitosis, interferes with HP1-H3K9me3 interaction, and therefore, ejects HP1 from its binding site [22].

Physical interactions of CBX5

• Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression [10].
• We show here that the chromo shadow domain mediates the self-associations of HP1-type proteins and is also necessary for binding to LBR both in vitro and in the yeast two-hybrid assay [15].
• The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure [17].

Regulatory relationships of CBX5

• Indeed, the subnuclear distribution of Orc1p is not affected by treatments that trigger the dispersal of HP1 [23].
• CBX5 has antisense Alu elements in its 3'UTR region, making it susceptible to the regulation of other protein-coding RNAs with sense Alu elements, and Pol-III transcribed Alus [24].

Other interactions of CBX5

• We have adapted the DamID method to systematically identify target genes of the heterochromatin proteins HP1 and SUV39H1 in human and mouse cells [25].
• Isoform-specific interaction of HP1 with human TAFII130 [26].
• Here we report that MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1 (HP1), an adaptor protein that recognizes methylated lysines within histone tails and mediates transcriptional repression by recruiting histone methyltransferase [27].
• Since the histone methyl-lysine residues recognized by HP1 also serve as substrates for deacetylation by HDACs, the interaction of MITR and HDACs with HP1 provides an efficient mechanism for silencing MEF2 target genes by coupling histone deacetylation and methylation [27].
• We observed that, in a large proportion of ICF G2 nuclei, all HP1 isoforms show an aberrant signal concentrated into a prominent bright focus that co-localizes with the undercondensed 1qh or 16qh heterochromatin [28].

Analytical, diagnostic and therapeutic context of CBX5

• Gel filtration, gel overlay experiments, and mass spectroscopy show that HP1 proteins can self-associate, and we suggest that it is as oligomers that HP1 proteins are incorporated into heterochromatin complexes that silence gene activity [29].
• The DNA-binding activity of the recombinant HP1 was demonstrated by gel mobility shift assay and South-Western-type blotting [4].

References