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Deregulation of Epigenetic Mechanisms by the Hepatitis B Virus X Protein in Hepatocarcinogenesis  [PDF]
Ourania M. Andrisani
Viruses , 2013, DOI: 10.3390/v5030858
Abstract: This review focuses on the significance of deregulation of epigenetic mechanisms by the hepatitis B virus (HBV) X protein in hepatocarcinogenesis and HBV replication. Epigenetic mechanisms, DNA methylation, and specific histone modifications, e.g., trimethylation of H3 on lysine-27 or lysine-4, maintain ‘cellular memory’ by silencing expression of lineage-inducing factors in stem cells and conversely, of pluripotency factors in differentiated cells. The X protein has been reported to induce expression of DNA methyltransferases (DNMTs), likely promoting epigenetic changes during hepatocarcinogenesis. Furthermore, in cellular and animal models of X-mediated oncogenic transformation, protein levels of chromatin modifying proteins Suz12 and Znf198 are down-regulated. Suz12 is essential for the Polycomb Repressive Complex 2 (PRC2) mediating the repressive trimethylation of H3 on lysine-27 (H3K27me3). Znf198, stabilizes the LSD1-CoREST-HDAC complex that removes, via lysine demethylase1 (LSD1), the activating trimethylation of H3 on lysine-4 (H3K4me3). Down-regulation of Suz12 also occurs in liver tumors of woodchucks chronically infected by woodchuck hepatitis virus, an animal model recapitulating HBV-mediated hepatocarcinogenesis in humans. Significantly, subgroups of HBV-induced liver cancer re-express hepatoblast and fetal markers, and imprinted genes, suggesting hepatocyte reprogramming during oncogenic transformation. Lastly, down-regulation of Suz12 and Znf198 enhances HBV replication. Collectively, these observations suggest deregulation of epigenetic mechanisms by HBV X protein influences both the viral cycle and the host cell.
A Newly Uncovered Group of Distantly Related Lysine Methyltransferases Preferentially Interact with Molecular Chaperones to Regulate Their Activity  [PDF]
Philippe Cloutier,Mathieu Lavallée-Adam,Denis Faubert,Mathieu Blanchette,Benoit Coulombe
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003210
Abstract: Methylation is a post-translational modification that can affect numerous features of proteins, notably cellular localization, turnover, activity, and molecular interactions. Recent genome-wide analyses have considerably extended the list of human genes encoding putative methyltransferases. Studies on protein methyltransferases have revealed that the regulatory function of methylation is not limited to epigenetics, with many non-histone substrates now being discovered. We present here our findings on a novel family of distantly related putative methyltransferases. Affinity purification coupled to mass spectrometry shows a marked preference for these proteins to associate with various chaperones. Based on the spectral data, we were able to identify methylation sites in substrates, notably trimethylation of K135 of KIN/Kin17, K561 of HSPA8/Hsc70 as well as corresponding lysine residues in other Hsp70 isoforms, and K315 of VCP/p97. All modification sites were subsequently confirmed in vitro. In the case of VCP, methylation by METTL21D was stimulated by the addition of the UBX cofactor ASPSCR1, which we show directly interacts with the methyltransferase. This stimulatory effect was lost when we used VCP mutants (R155H, R159G, and R191Q) known to cause Inclusion Body Myopathy with Paget's disease of bone and Fronto-temporal Dementia (IBMPFD) and/or familial Amyotrophic Lateral Sclerosis (ALS). Lysine 315 falls in proximity to the Walker B motif of VCP's first ATPase/D1 domain. Our results indicate that methylation of this site negatively impacts its ATPase activity. Overall, this report uncovers a new role for protein methylation as a regulatory pathway for molecular chaperones and defines a novel regulatory mechanism for the chaperone VCP, whose deregulation is causative of degenerative neuromuscular diseases.
SET/MYND Lysine Methyltransferases Regulate Gene Transcription and Protein Activity  [PDF]
Kristin Leinhart,Mark Brown
Genes , 2011, DOI: 10.3390/genes2010210
Abstract: The SET and MYND (SMYD) family of lysine methyltransferases is defined by a SET domain that is split into two segments by a MYND domain, followed by a cysteine-rich post-SET domain. While members of the SMYD family are important in the SET-mediated regulation of gene transcription, pathological consequences have also been associated with aberrant expression of SMYD proteins. The last decade has witnessed a rapid increase in the studies and corresponding understanding of these highly impactful enzymes. Herein, we review the current body of knowledge related to the SMYD family of?lysine methyltransferases and their role in transcriptional regulation, epigenetics, and?tumorigenesis.
The SET-domain protein superfamily: protein lysine methyltransferases
Shane C Dillon, Xing Zhang, Raymond C Trievel, Xiaodong Cheng
Genome Biology , 2005, DOI: 10.1186/gb-2005-6-8-227
Abstract: Nucleosomes, the main components of chromatin, consist of histones, and histone proteins have positively charged amino-terminal tails that are exposed on the outside of nucleosomes. These tails are subject to several post-translational covalent modifications, including acetylation, phosphorylation, ubiquitination, sumoylation and methylation (reviewed in [1]). Methylation been found on a range of lysine residues in various histones: K4 (using the single-letter amino-acid code for lysine), K9, K27, K36 and K79 in histone H3, K20 in histone H4, K59 in the globular domain of histone H4 [2] and K26 of histone H1B [3]. Several proteins responsible for the methylation of specific residues have been characterized, and all but one of these contains a SET domain; they make up the SET-domain protein methyltransferase family (Table 1). The exception to the rule is the DOT1 family, members of which methylate K79 in the globular region of histone H3 and which are structurally not related to SET-domain proteins [4-6]. Recent work suggests that SET-domain-containing proteins methylate a few proteins in addition to histones (see later); they should therefore be named protein lysine methyltransferases rather than histone lysine methyltransferases. The function of SET-domain proteins is to transfer a methyl group from S-adenosyl-L-methionine (AdoMet) to the amino group of a lysine residue on the histone or other protein, leaving a methylated lysine residue and the cofactor byproduct S-adenosyl-L-homocysteine (AdoHcy). Methylation of specific histone lysine residues serves as a post-translational epigenetic modification that controls the expression of genes by serving as 'markers' for the recruitment of particular complexes that direct the organization of chromatin.The SET domain (Figure 1) was first recognized as a conserved sequence in three Drosophila melanogaster proteins: a modifier of position-effect variegation, Suppressor of variegation 3-9 (Su(var)3-9) [7], the Polycomb-group
Age-Specific Differences in Oncogenic Pathway Deregulation Seen in Human Breast Tumors  [PDF]
Carey K. Anders, Chaitanya R. Acharya, David S. Hsu, Gloria Broadwater, Katherine Garman, John A. Foekens, Yi Zhang, Yixin Wang, Kelly Marcom, Jeffrey R. Marks, Sayan Mukherjee, Joseph R. Nevins, Kimberly L. Blackwell, Anil Potti
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001373
Abstract: Purpose To define the biology driving the aggressive nature of breast cancer arising in young women. Experimental Design Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young ≤45 years; older ≥65 years), 411 eligible patients (n = 200≤45 years; n = 211≥65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. Results In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and β-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and β-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value. Conclusion Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.
Changes in cortical cytoskeletal and extracellular matrix gene expression in prostate cancer are related to oncogenic ERG deregulation
Wolfgang A Schulz, Marc Ingenwerth, Carolle E Djuidje, Christiane Hader, J?rg Rahnenführer, Rainer Engers
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-505
Abstract: Expression of EPB41L1, EPB41L2, EPB41L3 (protein: 4.1B), EPB41L4B (EHM2), EPB41L5, EPB49 (dematin), VIL2 (ezrin), and DLG1 (summarized as ?cortical cytoskeleton" genes) as well as ERG was measured by quantitative RT-PCR in a well-characterized set of 45 M0 prostate adenocarcinoma and 13 benign tissues. Hypermethylation of EPB41L3 and GSTP1 was compared in 93 cancer tissues by methylation-specific PCR. Expression of 4.1B was further studied by immunohistochemistry.EPB41L1 and EPB41L3 were significantly downregulated and EPB41L4B was upregulated in cancer tissues. Low EPB41L1 or high EPB41L4B expression were associated with earlier biochemical recurrence. None of the other cortical cytoskeleton genes displayed expression changes, in particular EPB49 and VIL2, despite hints from previous studies. EPB41L3 downregulation was significantly associated with hypermethylation of its promoter and strongly correlated with GSTP1 hypermethylation. Protein 4.1B was detected most strongly in the basal cells of normal prostate epithelia. Its expression in carcinoma cells was similar to the weaker one in normal luminal cells. EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. Expression changes in EPB41L3 and EPB41L4B closely paralleled those previously observed for the extracellular matrix genes FBLN1 and SPOCK1, respectively.Specific changes in the cortical cytoskeleton were observed during prostate cancer progression. They parallel changes in the expression of extracellular matrix components and all together appear to be associated with oncogenic ERG overexpression. We hypothesize that these alterations may contribute to the increased invasivity conferred to prostate cancer cells by ERG deregulation.The progression of epithelial tumors to invasive carcinomas involves changes in cell polarity, adhesion and motility that permit the detachment of cancer cells from the epithelial layer, their invasion into adjacent tis
Solution Structure of MSL2 CXC Domain Reveals an Unusual Zn3Cys9 Cluster and Similarity to Pre-SET Domains of Histone Lysine Methyltransferases  [PDF]
Sanduo Zheng, Jia Wang, Yingang Feng, Jinfeng Wang, Keqiong Ye
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045437
Abstract: The dosage compensation complex (DCC) binds to single X chromosomes in Drosophila males and increases the transcription level of X-linked genes by approximately twofold. Male-specific lethal 2 (MSL2) together with MSL1 mediates the initial recruitment of the DCC to high-affinity sites in the X chromosome. MSL2 contains a DNA-binding cysteine-rich CXC domain that is important for X targeting. In this study, we determined the solution structure of MSL2 CXC domain by NMR spectroscopy. We identified three zinc ions in the CXC domain and determined the metal-to-cysteine connectivities from 1H-113Cd correlation experiments. The structure reveals an unusual zinc-cysteine cluster composed of three zinc ions coordinated by six terminal and three bridging cysteines. The CXC domain exhibits unexpected structural homology to pre-SET motifs of histone lysine methyltransferases, expanding the distribution and structural diversity of the CXC domain superfamily. Our findings provide novel structural insight into the evolution and function of CXC domains.
Methylation of phytohormones by the SABATH methyltransferases
LiJia Qu,Shuang Li,ShuFan Xing
Chinese Science Bulletin , 2010, DOI: 10.1007/s11434-010-3245-x
Abstract: In plants, one of the most common modifications of secondary metabolites is methylation catalyzed by various methyltransferases. Recently, a new class of methyltransferases, the SABATH family of methyltransferases, was found to modify phytohormones and other small molecules. The SABATH methyltransferases share little sequence similarity with other well characterized methyltransferases. Arabidopsis has 24 members of the SABATH methyltransferase genes, and a subset of them has been shown to catalyze the formation of methyl esters with phytohormones and other small molecules. Physiological and genetic analyses show that methylation of phytohormones plays important roles in regulating various biological processes in plants, including stress responses, leaf development, and seed maturation/germination. In this review, we focus on phytohormone methylation by the SABATH family methyltransferases and the implication of these modifications in plant development.
Structure of the Catalytic Domain of EZH2 Reveals Conformational Plasticity in Cofactor and Substrate Binding Sites and Explains Oncogenic Mutations  [PDF]
Hong Wu, Hong Zeng, Aiping Dong, Fengling Li, Hao He, Guillermo Senisterra, Alma Seitova, Shili Duan, Peter J. Brown, Masoud Vedadi, Cheryl H. Arrowsmith, Matthieu Schapira
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083737
Abstract: Polycomb repressive complex 2 (PRC2) is an important regulator of cellular differentiation and cell type identity. Overexpression or activating mutations of EZH2, the catalytic component of the PRC2 complex, are linked to hyper-trimethylation of lysine 27 of histone H3 (H3K27me3) in many cancers. Potent EZH2 inhibitors that reduce levels of H3K27me3 kill mutant lymphoma cells and are efficacious in a mouse xenograft model of malignant rhabdoid tumors. Unlike most SET domain methyltransferases, EZH2 requires PRC2 components, SUZ12 and EED, for activity, but the mechanism by which catalysis is promoted in the PRC2 complex is unknown. We solved the 2.0 ? crystal structure of the EZH2 methyltransferase domain revealing that most of the canonical structural features of SET domain methyltransferase structures are conserved. The site of methyl transfer is in a catalytically competent state, and the structure clarifies the structural mechanism underlying oncogenic hyper-trimethylation of H3K27 in tumors harboring mutations at Y641 or A677. On the other hand, the I-SET and post-SET domains occupy atypical positions relative to the core SET domain resulting in incomplete formation of the cofactor binding site and occlusion of the substrate binding groove. A novel CXC domain N-terminal to the SET domain may contribute to the apparent inactive conformation. We propose that protein interactions within the PRC2 complex modulate the trajectory of the post-SET and I-SET domains of EZH2 in favor of a catalytically competent conformation.
Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex
Mark A Brown, Robert J Sims, Paul D Gottlieb, Philip W Tucker
Molecular Cancer , 2006, DOI: 10.1186/1476-4598-5-26
Abstract: Smyd2 mRNA is most highly expressed in heart and brain tissue, as demonstrated by northern analysis and in situ hybridization. Over-expressed Smyd2 localizes to the cytoplasm and the nucleus in 293T cells. Although accumulating evidence suggests that methylation of histone 3, lysine 36 (H3K36) is associated with actively transcribed genes, we show that the SET domain of Smyd2 mediates H3K36 dimethylation and that Smyd2 represses transcription from an SV40-luciferase reporter. Smyd2 associates specifically with the Sin3A histone deacetylase complex, which was recently linked to H3K36 methylation within the coding regions of active genes in yeast. Finally, we report that exogenous expression of Smyd2 suppresses cell proliferation.We propose that Sin3A-mediated deacetylation within the coding regions of active genes is directly linked to the histone methyltransferase activity of Smyd2. Moreover, Smyd2 appears to restrain cell proliferation, likely through direct modulation of chromatin structure.Cell proliferation and differentiation are coordinated by synchronized patterns of gene expression. The regulation of these patterns is achieved, in part, through epigenetic mechanisms that affect the nature of DNA packaging into chromatin [1]. Specifically, post-translational covalent modifications to histone tails impact the structural dynamics of the nucleosome, thereby affecting DNA accessibility to transcriptional complexes [2-4]. Common modifications to histones include methylation, acetylation, phosphorylation, and ubiquitination [5]. Importantly, alterations in global levels of histone methylation and acetylation are connected to the biology of cancerous lesions and their clinical outcome [6]. A number of histone lysine methyltransferases (HKMTs) are disrupted in a variety of cancer types [7,8]. How histone methylation mechanistically contributes to the oncogenic state is poorly understood.All known HKMTs, with one exception [5], catalyze methyl transfer via the SET dom
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