Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.37 (DNA methyltransferase)
4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A chromosomal translocation, t(4;11)-(q21;q23), is associated with an aggressive mixed-lineage leukemia. A yeast artificial chromosome was used to clone the chromosomal breakpoint of this translocation in the RS4;11 cell line. The breakpoint sequences revealed an inverted repeat bordered by a consensus site for topoisomerase II binding and cleavage as well as chi-like elements. The der(11) chromosome encodes a fusion RNA and predicted chimeric protein between the 11q23 gene MLL and a 4q21 gene designated AF4. The sequence of the complete open reading frame for this fusion transcript reveals the MLL protein to have homology with DNA methyltransferase, the Drosophila trithorax gene product, and the "AT-hook" motif of high-mobility-group proteins. An alternative splice that deletes the AT-hook region of MLL was identified. AF4 is a serine- and proline-rich putative transcription factor with a glutamine-rich carboxyl terminus. The composition of the complete MLL-AF4 fusion product argues that it may act through either a gain-of-function or a dominant negative mechanism in leukemogenesis.
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PMID:Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product. 768 31

The ALLI gene, located at chromosome band 11q23, is involved in acute leukemia through a series of chromosome translocations and fusion to a variety of genes, most frequently to A4 and AF9. The fused genes encode chimeric proteins proteins. Because the Drosophila homologue of ALL1, trithorax, is a positive regulator of homeotic genes and acts at the level of transcription, it is conceivable that alterations in ALL1 transcriptional activity may underlie its action in malignant transformation. To begin studying this, we examined the All1, AF4, AF9, and AF17 proteins for the presence of potential transcriptional regulatory domains. This was done by fusing regions of the proteins to the yeast GAL4 DNA binding domain and assaying their effect on transcription of a reporter gene. A domain of 55 residues positioned at amino acids 2829-2883 of ALL1 was identified as a very strong activator. Further analysis of this domain by in vitro mutagenesis pointed to a core of hydrophobic and acidic residues as critical for the activity. An ALL1 domain that repressed transcription of the reporter gene coincided with the sequence homologous to a segment of DNA methyltransferase. An AF4 polypeptide containing residues 480-560 showed strong activation potential. The C-terminal segment of AF9 spanning amino acids 478-568 transactivated transcription of the reporter gene in HeLa but not in NIH 3T3 cells. These results suggest that ALL1, AF4, and probably AF9 interact with the transcriptional machinery of the cell.
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PMID:Domains with transcriptional regulatory activity within the ALL1 and AF4 proteins involved in acute leukemia. 861 64

While it is now accepted that methylation of cytosine residues plays a role in various epigenetic phenomena in mammals and flowering plants, the involvement of methylation patterns in the regulation of normal development has remained a controversial and essentially untested issue in the 20 years since such a role was first proposed. Antisense suppression of a DNA methyltransferase in Arabidopsis and characterization of methylation-defective mutants of Arabidopsis have shown that perturbations of methylation patterns disrupt the development of plants, and targeted mutation of the murine gene that encodes the one known from of DNA methyltransferase has shown that methylation is required for cellular differentiation, genomic imprinting, and X chromosome inactivation in mammals. Ectopic expression of homeotic genes and homeotic transformations of floral organs in methylation-defective plants suggest that (in plants and perhaps mammals) heritable methylation patterns reinforce and may have supplanted heritable gene control mediated by chromosomal proteins of the Polycomb and trithorax groups. It is also possible that the developmental abnormalities are the result of ectopic gene expression caused by activation of transcription from nearby parasitic sequence elements that are normally repressed by methylation. Application of modern methods of genetic analysis promises to give definite answers to long-standing questions as to the roles and significance of genomic methylation patterns in normal development and genome defense.
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PMID:Genetic analysis of genomic methylation patterns in plants and mammals. 892 87

The DNA methyltransferase Dnmt1 is responsible for cytosine methylation in mammals and has a role in gene silencing. DNA methylation represses genes partly by recruitment of the methyl-CpG-binding protein MeCP2, which in turn recruits a histone deacetylase activity. Here we show that Dnmt1 is itself associated with histone deacetylase activity in vivo. Consistent with this association, we find that one of the known histone deacetylases, HDAC1, has the ability to bind Dnmt1 and can purify methyltransferase activity from nuclear extracts. We have identified a transcriptional repression domain in Dnmt1 that functions, at least partly, by recruiting histone deacetylase activity and shows homology to the repressor domain of the trithorax-related protein HRX (also known as MLL and ALL-1). Our data show a more direct connection between DNA methylation and histone deacetylation than was previously considered. We suggest that the process of DNA methylation, mediated by Dnmt1, may depend on or generate an altered chromatin state via histone deacetylase activity.
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PMID:DNA methyltransferase Dnmt1 associates with histone deacetylase activity. 1061 35

Ligand screening was utilized to isolate a human cDNA that encodes a novel CpG binding protein, human CpG binding protein (hCGBP). This factor contains three cysteine-rich domains, two of which exhibit homology to the plant homeodomain finger domain. A third cysteine-rich domain conforms to the CXXC motif identified in DNA methyltransferase, human trithorax, and methyl-CpG binding domain protein 1. A fragment of hCGBP that contains the CXXC domain binds to an oligonucleotide probe containing a single CpG site, and this complex is disrupted by distinct oligonucleotide competitors that also contain a CpG motif(s). However, hCGBP fails to bind oligonucleotides in which the CpG motif is either mutated or methylated, and it does not bind to single-stranded DNA or RNA probes. Furthermore, the introduction of a CpG dinucleotide into an unrelated oligonucleotide sequence is sufficient to produce a binding site for hCGBP. Native hCGBP is detected as an 88-kDa protein by Western analysis and is ubiquitously expressed. The DNA-binding activity of native hCGBP is apparent in electrophoretic mobility shift assays, and hCGBP trans-activates promoters that contain CpG motifs but not promoters in which the CpG is ablated. These data indicate that hCGBP is a transcriptional activator that recognizes unmethylated CpG dinucleotides, suggesting a role in modulating the expression of genes located within CpG islands.
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PMID:Cloning of a mammalian transcriptional activator that binds unmethylated CpG motifs and shares a CXXC domain with DNA methyltransferase, human trithorax, and methyl-CpG binding domain protein 1. 1068 57

Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos-like phenotype. We evaluated a three-generation family segregating a Sotos-like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DNA methyltransferase gene (DNMT1), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.
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PMID:19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression. 2120 97

Epigenetic marks, such as histone modifications or DNA methylation, regulate tissue specific gene expression by affecting the structures and accessibility of chromatin or DNA. Epigenetics, the molecular mechanisms regulating the epigenome, would therefore be critically involved in development and cell differentiation versus proliferation. Histone modifications include methylation, acetylation, phosphorylation and ubiquitination of specific lysine, arginine or serine residues on histone tails, and each modification has its own specific effect on gene expressions. Modification of histones is accomplished by multimeric protein complexes including polycomb and trithorax group proteins. Regulation of DNA methylation is another mechanism of epigenetic regulation, which is achieved by DNA methyltransferase (DNMT) and TET family proteins. Methylation of cysteine residues on DNA generally leads to transcriptional repression, and oxidation of methylated cysteines provides another type of molecular mark on DNA that regulates gene expression. Next generation sequencing of tumor genomes has uncovered recurrent somatic mutations of epigenetic genes such as DNMT3A, TET2, and ASXL1 in hematologic malignancies, showing that epigenetic dysregulation is a critical step leading to the transformation of hematopoietic cells. Rigorous integrated functional analyses of mutated epigenetic genes are currently underway, and are anticipated to lead to the development of novel molecularly targeted therapies for hematologic malignancies.
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PMID:A primer for epigenetics of hematological malignancies. 2772 78

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