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46-590: 4MI0 , 4MI5 , 5HYN , 5IJ8 , 5IJ7 2146 14056 ENSG00000106462 ENSMUSG00000029687 Q15910 Q61188 NM_001203247 NM_001203248 NM_001203249 NM_004456 NM_152998 NM_001146689 NM_007971 NP_001190176 NP_001190177 NP_001190178 NP_004447 NP_694543 NP_001140161 NP_031997 Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme ( EC 2.1.1.43 ) encoded by EZH2 gene , that participates in histone methylation and, ultimately, transcriptional repression . EZH2 catalyzes

92-413: A clinically relevant mutation of residue tyrosine 641 to phenylalanine (Y641F) results in higher H3K27 tri-methylation activity. It is proposed that the removal of the hydroxyl group on Y641 abrogates steric hindrance and allows for accommodation of a third methyl group on the substrate lysine. EZH2 is an attractive target for anti-cancer therapy because it helps cancerous cells divide and proliferate. It

138-589: A complex with at least two other PRC2 components, SUZ12 and EED . As a histone methyltransferase (HMTase), EZH2's primary function is to methylate Lys-27 on histone 3 (H3K27me) by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM). EZH2 is capable of mono-, di-, and tri- methylation of H3K27 and has been associated with a variety of biological functions, including transcriptional regulation in hematopoiesis , development, and cell differentiation . EZH2 has also been identified as capable of methylating non- histone proteins. EZH2, as

184-539: A decrease in EZH2 activity. Phosphorylation of T492 has been suggested to disrupt contacts between human EZH2 and its binding partners in the PRC2 complex, thus hindering its catalytic activity. In addition to phosphorylation, it has also been shown that PRC2/EZH2-EED activity is antagonized by transcription-activating histone marks, such as acetylation of H3K27 ( H3K27ac ) and methylation of H3K36 ( H3K36me ). EZH2 expression

230-405: A part of PRC2, catalyzes trimethylation of H3K27 ( H3K27me3 ), which is a histone modification that has been characterized as part of the histone code . The histone code is the theory that chemical modifications, such as methylation , acetylation , and ubiquitination , of histone proteins play distinctive roles in epigenetic regulation of gene transcription . EZH2-mediated catalysis of H3K27me3

276-443: A phenyl ring of a phenylalanine. A glutamate on a nearby loop interacts with nitrogens on the target arginine residue. This interaction redistributes the positive charge and leads to the deprotonation of one nitrogen group, which can then make a nucleophilic attack on the methyl group of SAM. Differences between the two types of PRMTs determine the next methylation step: either catalyzing the dimethylation of one nitrogen or allowing

322-631: A rare disorder characterized by advanced bone age, macrocephaly , and hypertelorism . The histidine residue in the active site of the wild-type EZH2 was mutated to tyrosine in patients diagnosed with Weaver syndrome. The mutation likely interferes with cofactor binding and causes disruption of the natural function of the protein. Enhancer of zeste (E(z)) was originally identified in Drosophila melanogaster , and its mammalian homologs were subsequently identified and named EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2). EZH2

368-606: A role in activation of transcription, independently of PRC2 . In breast cancer cells, EZH2 has been demonstrated to activate NF-κB target genes, which are involved in responses to stimuli. The functional role of this activity and its mechanism are still unknown. EZH2 plays an essential role in development. In particular, it helps control transcriptional repression of genes that regulate cell differentiation. In embryonic stem cells, EZH2-mediated trimethylation of H3K27me3 in regions containing developmental genes appears to be important for maintenance of normal cell differentiation. H3K27me3

414-404: A study performed by Zhaomei Mu and his associates concluded that the knockdown gene for EZH2 inhibited both the migration and invasion of IBC cells. Also in vivo , its knockdown gene suppressed tumor growth, most likely by the presence of fewer blood vessels, or reduced angiogenesis, in the EZH2 knockdown tumor versus EZH2 tumors. Mutations in the EZH2 gene have been linked with Weaver syndrome ,

460-696: Is a protein that in humans is encoded by the SUZ12 gene . This zinc finger gene has been identified at the breakpoints of a recurrent chromosomal translocation reported in endometrial stromal sarcoma. Recombination of these breakpoints results in the fusion of this gene and JAZF1 . The protein encoded by this gene contains a zinc finger domain in the C terminus of the coding region. The specific function of this gene has not yet been determined. SUZ12, as part of Polycomb Repressive Complex 2 ( PRC2 ), may be involved with chromatin silencing in conjunction with HOTAIR ncRNA, using its zinc-finger domain to bind

506-783: Is a viable area of cancer research. EZH2 inhibitor development has focused on targeting the SET domain active site of the protein. Several inhibitors of EZH2 have been developed as of 2015, including 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, and UNC1999. Combination therapies are being studied as possible treatments when primary treatments begin to fail. Etoposide , a topoisomerase inhibitor, when combined with an EZH2 inhibitor, becomes more effective for non-small cell lung cancers with BRG1 and EGFR mutations. However, EZH2 and lysine methylation can have tumor suppressing activity, for example in myelodysplastic syndrome , indicating that EZH2 inhibition may not be beneficial in all cases. EZH2

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552-490: Is also important in driving X-inactivation , the silencing of one X-chromosome in females during development. During X-inactivation, it is thought that EZH2 is involved in initiating heterochromatin formation by trimethylating H3K27 and that other histone methyltransferases and histone marks may be involved in maintaining the silenced state. Further, EZH2 has been identified as an essential protein involved in development and differentiation of B-cells and T-cells . H3K27me3

598-430: Is associated with long term transcription repression. EZH2, as well as other Polycomb group proteins, are involved in establishing and maintaining gene repression through cell division . This transcriptionally repressive state is thought to be due to PRC2/EZH2-EED-mediated H3K27 methylation and subsequent recruitment of PRC1 which facilitates condensation of chromatin and formation of heterochromatin . Heterochromatin

644-459: Is crucial for epigenetic regulation of specific patterning during osteochondrogenesis, or bone and cartilage development, of the craniofacial skeletal elements. By repressing inhibitors, EZH2 promotes bone and cartilage formation in facial skeletal features arising from the neural crest. Above average EZH2 expression has become a biological marker for the most aggressive form for breast cancer known as Inflammatory Breast Cancer (IBC). But in 2013,

690-476: Is found in larger amounts than in healthy cells in a wide range of cancers including breast, prostate, bladder, uterine , and renal cancers, as well as melanoma and lymphoma . EZH2 is a gene suppressor, so when it becomes overexpressed, many tumor suppressor genes that are normally turned on, are turned off. Inhibition of EZH2 function shrinks malignant tumors in some reported cases because those tumor suppressor genes are not silenced by EZH2. EZH2 typically

736-496: Is highly conserved through evolution . It and its homologs play essential roles in development, cell differentiation, and cell division in plants, insects, fish, and mammals. The following taxonomic tree is a depiction of EZH2's distribution throughout a wide variety of species. Histone methyltransferase The class of lysine-specific histone methyltransferases is subdivided into SET domain-containing and non-SET domain-containing. As indicated by their monikers, these differ in

782-464: Is highly upregulated. Methylation is the addition of a -CH 3 , or methyl group, to another molecule. In biology, methylation is typically catalyzed by enzymes, and methyl groups are commonly added to either proteins or nucleic acids. In EZH2-catalyzed methylation, the amino acid lysine in the histone h3 is methylated. This amino acid residue can be methylated up to three times on its terminal ammonium group. These methylated lysines are important in

828-456: Is involved in suppressing genes that promote differentiation, thus maintaining an undifferentiated state of B- and T-cells and playing an important role in regulating hematopoiesis . The activity of EZH2 is regulated by the post-translational phosphorylation of threonine and serine residues on EZH2. Specifically, phosphorylation of T350 has been linked to an increase in EZH2 activity while phosphorylation of T492 and S21 have been linked to

874-406: Is not expressed in healthy adults; it is only found in actively dividing cells, like those active during fetal development. Because of this characteristic, overexpression of EZH2 can be used as a diagnostic marker of cancer and some neurodegenerative disorders. However, there are cases where it is difficult to tell whether overexpression of EZH2 is the cause of a disease, or simply a consequence. If it

920-569: Is not yet compelling evidence that suggests cancers develop purely by abnormalities in histone methylation or its signaling pathways, however they may be a contributing factor. For example, down-regulation of methylation of lysine 9 on histone 3 (H3K9me3) has been observed in several types of human cancer (such as colorectal cancer, ovarian cancer, and lung cancer), which arise from either the deficiency of H3K9 methyltransferases or elevated activity or expression of H3K9 demethylases. The methylation of histone lysine has an important role in choosing

966-422: Is only a consequence, targeting EZH2 for inhibition may not cure the disease. One example of a cancer pathway in which EZH2 plays a role is the pRB-E2F pathway. It is downstream from the pRB-E2F pathway, and signals from this pathway lead to EZH2 overexpression. Another important characteristic of EZH2 is that when EZH2 is overexpressed, it can activate genes without forming PRC2 . This is an issue because it means

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1012-596: Is regulated by estrogen signaling in human normal breast epithelium and human breast cancers. EZH2 function is highly dependent upon its recruitment by the PRC2 complex. In particular, WD40-repeat protein embryonic ectoderm development (EED) and zinc finger protein suppressor of zeste 12 (SUZ12) are needed to stabilize the interaction of EZH2 with its histone substrate Recently, two isoforms of EZH2 generated from alternative splicing have been identified in humans: EZH2α and EZH2β. Both isoforms contain elements that have been identified as important for EZH2 function including

1058-591: Is responsible for healthy embryonic development through the epigenetic maintenance of genes responsible for regulating development and differentiation . EZH2 is responsible for the methylation activity of PRC2, and the complex also contains proteins required for optimal function ( EED , SUZ12 , JARID2 , AEBP2 , RbAp46/48 , and PCL ). Mutation or over-expression of EZH2 has been linked to many forms of cancer. EZH2 inhibits genes responsible for suppressing tumor development, and blocking EZH2 activity may slow tumor growth. EZH2 has been targeted for inhibition because it

1104-639: Is tightly packed chromatin which limits the accessibility of transcription machinery to the underlying DNA, thereby suppressing transcription. During cell division, heterochromatin formation is required for proper chromosome segregation . PRC2/EED-EZH2 complex may also be involved in the recruitment of DNA methyltransferases ( DNMTs ), which results in increased DNA methylation , another epigenetic layer of transcription repression. Specific genes that have been identified as targets of EZH2-mediated transcriptional repression include HOXA9 , HOXC8 , MYT1 , CDKN2A and retinoic acid target genes. In cancer, EZH2 may play

1150-550: Is upregulated in multiple cancers including, but not limited to, breast, prostate , melanoma , and bladder cancer. Mutations in the EZH2 gene are also associated with Weaver syndrome , a rare congenital disorder, and EZH2 is involved in causing neurodegenerative symptoms in the nervous system disorder, ataxia telangiectasia . EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). EZH2's catalytic activity relies on its formation of

1196-460: The active site of the enzyme. This orientation of substrate and cofactor allows SAM to dissociate without disrupting substrate binding and can lead to multiple rounds of lysine methylation without substrate dissociation. Although neither a substrate-bound or SAM-bound crystal structure for EZH2 has been determined, STAMP structure alignment with the human SET7/9 methyltransferase shows conserved tyrosine residues in almost identical positions within

1242-587: The nuclear localization signal , the EED and SUZ12 binding sites as well as the conserved SET domain. Most studies have thus far focused on the longer isoform EZH2α, but EZH2β, which lacks exons 4 and 8, has been shown to be active. Furthermore, PRC2/EZH2β complexes act on distinct genes from that of its PRC2/EZH2α counterpart suggesting that each isoform may act to regulate a specific subset of genes. Additional evidence suggests that EZH2 may also be capable of lysine methylation independent of association with PRC2, when EZH2

1288-470: The SET domain methyltransferases to target many different residues. This interplay between the pre-SET domain and the catalytic core is critical for enzyme function. In order for the reaction to proceed, S-Adenosyl methionine (SAM) and the lysine residue of the substrate histone tail must first be bound and properly oriented in the catalytic pocket of the SET domain. Next, a nearby tyrosine residue deprotonates

1334-485: The addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine . Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis. EZH2 is the functional enzymatic component of the Polycomb Repressive Complex 2 ( PRC2 ), which

1380-399: The arginine binding pocket. The catalytic domain of PRMTs consists of a SAM binding domain and substrate binding domain (about 310 amino acids in total). Each PRMT has a unique N-terminal region and a catalytic core. The arginine residue and SAM must be correctly oriented within the binding pocket. SAM is secured inside the pocket by a hydrophobic interaction between an adenine ring and

1426-472: The control of mammalian gene expression and have a functional role in heterochromatin formation, X-chromosome inactivation and transcriptional regulation. In mammalian chromosomes, histone lysine methylation can either activate or repress genes depending the site of methylation. Recent work has shown that at least part of the silencing function of the EZH2 complex is the methylation of histone H3 on lysine 27. Methylation, and other modifications, take place on

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1472-431: The effect of a histone methyltransferase on gene expression strongly depends on which histone residue it methylates. See Histone#Chromatin regulation . Abnormal expression or activity of methylation-regulating enzymes has been noted in some types of human cancers, suggesting associations between histone methylation and malignant transformation of cells or formation of tumors. In recent years, epigenetic modification of

1518-483: The function and regulation of histone methyltransferases in malignant transformation of cells, carcinogenesis of the tissue, and tumorigenesis. SUZ12 5IJ7 , 5IJ8 , 5HYN 23512 52615 ENSG00000178691 ENSMUSG00000017548 Q15022 Q80U70 NM_015355 NM_001321207 NM_001163018 NM_199196 NP_001308136 NP_056170 NP_001156490 NP_954666 Polycomb protein SUZ12

1564-583: The globular core of the histone, and is the only enzyme known to do so. A possible homolog of Dot1 was found in archaea which shows the ability to methylate archaeal histone-like protein in recent studies. The N terminal of Dot1 contains the active site. A loop serving as the binding site for SAM links the N-terminal and the C-terminal domains of the Dot1 catalytic domain. The C-terminal is important for

1610-418: The histone proteins, especially the methylation of the histone H3, in cancer development has been an area of emerging research. It is now generally accepted that in addition to genetic aberrations, cancer can be initiated by epigenetic changes in which gene expression is altered without genomic abnormalities. These epigenetic changes include loss or gain of methylations in both DNA and histone proteins. There

1656-567: The histones. Methyl modifications can affect the binding of proteins to these histones and either activate or inhibit transcription . EZH2 is a member of the SET domain family of lysine methyltransferases which function to add methyl groups to lysine side chains of substrate proteins. SET methyltransferases depend on a S-Adenosyl methionine (SAM) cofactor to act as a methyl donor for their catalytic activity. SET domain proteins differ from other SAM-dependent methyltransferases in that they bind their substrate and SAM cofactor on opposite sides of

1702-581: The methylation activity of the enzyme is not mediated by complex formation. In breast cancer cells, EZH2 activates genes that promote cell proliferation and survival. It can also activate regulatory genes like c-myc and cyclin D1 by interacting with Wnt signaling factors. Importantly, the mutation of tyrosine 641 in the active SET domain to a number of different amino acids is a common feature of some B-cell lymphomas. Developing an inhibitor of EZH2 and preventing unwanted histone methylation of tumor suppressor genes

1748-420: The pathway for repairing DNA double-strand breaks . As an example, tri-methylated H3K36 is required for homologous recombinational repair, while dimethylated H4K20 can recruit the 53BP1 protein for repair by the pathway of non-homologous end joining . Histone methyltransferase may be able to be used as biomarkers for the diagnosis and prognosis of cancers. Additionally, many questions still remain about

1794-474: The presence of a SET domain, which is a type of protein domain. Human genes encoding proteins with histone methyltransferase activity include: The structures involved in methyltransferase activity are the SET domain (composed of approximately 130 amino acids), the pre-SET, and the post-SET domains. The pre-SET and post-SET domains flank the SET domain on either side. The pre-SET region contains cysteine residues that form triangular zinc clusters, tightly binding

1840-411: The putative active site of EZH2. It had been previously suggested that tyrosine 726 in the EZH2 active site was acting as a general base to de-protonate the substrate lysine but kinetic isotope effects have indicated that active site residues are not directly involved in the chemistry of the methyltransferase reaction. Instead these experiments support a mechanism in which the residues lower the pKa of

1886-612: The site of methylation. For example, it is likely that the methylation of lysine 9 on histone H3 (H3K9me3) in the promoter region of genes prevents excessive expression of these genes and, therefore, delays cell cycle transition and/or proliferation. In contrast, methylation of histone residues H3K4, H3K36, and H3K79 is associated with transcriptionally active euchromatin. Depending on the site and symmetry of methylation, methylated arginines are considered activating (histone H4R3me2a, H3R2me2s, H3R17me2a, H3R26me2a) or repressive (H3R2me2a, H3R8me2a, H3R8me2s, H4R3me2s) histone marks. Generally,

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1932-504: The substrate lysine residue while simultaneously providing a channel for water to access the lysine side chain within the interior of the active site. Bulk solvent water can then easily deprotonate the lysine side chain, activating it for nucleophilic attack of the SAM cofactor in an S N 2 -like reaction resulting in transfer of the methyl group from SAM to the lysine side chain. EZH2 primarily catalyzes mono- and di-methylation of H3K27 but

1978-800: The substrate specificity and binding of Dot1 because the region carries a positive charge, allowing for a favorable interaction with the negatively charged backbone of DNA. Due to structural constraints, Dot1 is only able to methylate histone H3. There are three different types of protein arginine methyltransferases (PRMTs) and three types of methylation that can occur at arginine residues on histone tails. The first type of PRMTs ( PRMT1 , PRMT3 , CARM1 ⧸PRMT4, and Rmt1⧸Hmt1) produce monomethylarginine and asymmetric dimethylarginine (Rme2a). The second type (JBP1⧸ PRMT5 ) produces monomethyl or symmetric dimethylarginine (Rme2s). The third type (PRMT7) produces only monomethylated arginine. The differences in methylation patterns of PRMTs arise from restrictions in

2024-415: The symmetric methylation of both groups. However, in both cases the proton stripped from the nitrogen is dispersed through a histidine–aspartate proton relay system and released into the surrounding matrix. Histone methylation plays an important role in epigenetic gene regulation . Methylated histones can either repress or activate transcription as different experimental findings suggest, depending on

2070-417: The zinc atoms and stabilizing the structure. The SET domain itself contains a catalytic core rich in β-strands that, in turn, make up several regions of β-sheets. Often, the β-strands found in the pre-SET domain will form β-sheets with the β-strands of the SET domain, leading to slight variations to the SET domain structure. These small changes alter the target residue site specificity for methylation and allow

2116-417: The ε-amino group of the lysine residue. The lysine chain then makes a nucleophilic attack on the methyl group on the sulfur atom of the SAM molecule, transferring the methyl group to the lysine side chain. Instead of SET, non-SET domain-containing histone methyltransferase utilizes the enzyme Dot1. Unlike the SET domain, which targets the lysine tail region of the histone, Dot1 methylates a lysine residue in

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