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)

Recurrent translocation t(10;11) has been reported to be associated with acute myeloid leukemia (AML). Recently, two types of chimeric transcripts, MLL-AF10 in t(10;11)(p12;q23) and CALM-AF10 in t(10;11)(p13;q14), were isolated. t(10;11) is strongly associated with complex translocations, including invins(10;11) and inv(11)t(10;11), because the direction of transcription of AF10 is telomere to centromere. We analyzed a patient of AML with t(10;11)(p11.2;q23) and identified ABI-1 on chromosome 10p11.2, a human homolog to mouse Abl-interactor 1 (Abi-1), fused with MLL. Whereas the ABI-1 gene bears no homology with the partner genes of MLL previously described, the ABI-1 protein exhibits sequence similarity to protein of homeotic genes, contains several polyproline stretches, and includes a src homology 3 (SH3) domain at the C-terminus that is required for binding to Abl proteins in mouse Abi-1 protein. Recently, e3B1, an eps8 SH3 binding protein 1, was also isolated as a human homolog to mouse Abi-1. Three types of transcripts of ABI-1 gene were expressed in normal peripheral blood. Although e3B1 was considered to be a full-length ABI-1, the MLL-ABI-1 fusion transcript in this patient was formed by an alternatively spliced ABI-1. Others have shown that mouse Abi-1 suppresses v-ABL transforming activity and that e3B1, full-length ABI-1, regulates cell growth. In-frame MLL-ABI-1 fusion transcripts combine the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of alternatively spliced transcript of ABI-1. Our results suggest that the ABI-1 gene plays a role in leukemogenesis by translocating to MLL.
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PMID:ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23). 969 99

This manuscript tests the hypothesis that multiple forms of cytosine-DNA methyltransferase (MeTase) are expressed in vertebrates in vivo. Vertebrate genomes are distinguished by tissue- and gene-specific DNA methylation patterns. Specific methylation patterns are believed to encode epigenetic information. In distinction from the remarkable diversity of DNA methylation patterns, only one functional DNA MeTase cDNA has been identified to date in different vertebrate organisms. Using reverse transcription-polymerase chain reaction and RNase protection analyses, we show that the methyltransferase domain of the rat DNA MeTase is alternatively spliced in vivo, generating different in-frame variants of DNA MeTase in specific tissues. This process is developmentally regulated and is induced in PC12 cells by a known inducer of neuronal differentiation, nerve growth factor. The data presented here point toward a new mechanism for generating diversity of DNA MeTases and possibly diverse DNA methylation patterns.
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PMID:Multiple isoforms of DNA methyltransferase are encoded by the vertebrate cytosine DNA methyltransferase gene. 972 4

DNA methylation in mammals is required for embryonic development, X chromosome inactivation and imprinting. Previous studies have shown that methylation patterns become abnormal in malignant cells and may contribute to tumorigenesis by improper de novo methylation and silencing of the promoters for growth-regulatory genes. RNA and protein levels of the DNA methyltransferase DNMT1 have been shown to be elevated in tumors, however murine stem cells lacking Dnmt1 are still able to de novo methylate viral DNA. The recent cloning of a new family of DNA methyltransferases (Dnmt3a and Dnmt3b) in mouse which methylate hemimethylated and unmethylated templates with equal efficiencies make them candidates for the long sought de novo methyltransferases. We have investigated the expression of human DNMT1, 3a and 3b and found widespread, coordinate expression of all three transcripts in most normal tissues. Chromosomal mapping placed DNMT3a on chromosome 2p23 and DNMT3b on chromosome 20q11.2. Significant overexpression of DNMT3b was seen in tumors while DNMT1 and DNMT3a were only modestly over-expressed and with lower frequency. Lastly, several novel alternatively spliced forms of DNMT3b, which may have altered enzymatic activity, were found to be expressed in a tissue-specific manner.
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PMID:The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. 1032 16

Several alternatively spliced variants of DNA methyltransferase (DNMT) 3b have been described. Here, we identified new murine Dnmt3b mRNA isoforms and found that mouse embryonic stem (ES) cells expressed only Dnmt3b transcripts that contained exons 10 and 11, whereas the Dnmt3b transcripts in somatic cells lacked these exons, suggesting that this region is important for embryonic development. DNMT3b2 and 3b3 were the major isoforms expressed in human cell lines and the mRNA levels of these isoforms closely correlated with their protein levels. Although DNMT3b3 may be catalytically inactive, it still may be biologically important because D4Z4 and satellites 2 and 3 repeat sequences, all known DNMT3b target sequences, were methylated in cells that predominantly expressed DNMT3b3. Treatment of cells with the mechanism-based inhibitor 5-aza-2'-deoxycytidine (5-Aza-CdR) caused a complete depletion of DNMT1, 3a, 3b1, and 3b2 proteins. Human DNMT3b3 and the murine Dnmt3b3-like isoform, Dnmt3b6, were also depleted although less efficiently, suggesting that DNMT3b3 also may be capable of DNA binding. Moreover, de novo methylation of D4Z4 in T24 cancer cells after 5-Aza-CdR treatment only occurred when DNMT3b3 was expressed, reinforcing its role as a contributing factor of DNA methylation. The expression of either DNMT3b2 or 3b3, however, was not sufficient to explain the abnormal methylation of DNMT3b target sequences in human cancers, which may therefore be dependent on factors that affect DNMT3b targeting. Methylation analyses of immunodeficiency, chromosomal instabilities, and facial abnormalities cells revealed that an Alu repeat sequence was highly methylated, suggesting that Alu sequences are not DNMT3b targets.
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PMID:Role of the DNA methyltransferase variant DNMT3b3 in DNA methylation. 1475 47

Three methylated bases, 5-methylcytosine, N4-methylcytosine and N6-methyladenine (m6A), can be found in DNA. However, to date, only 5-methylcytosine has been detected in mammalian genomes. To reinvestigate the presence of m6A in mammalian DNA, we used a highly sensitive method capable of detecting one N6-methyldeoxyadenosine per million nucleosides. Our results suggest that the total mouse genome contains, if any, less than 10(3) m6A. Experiments were next performed on PRED28, a putative mammalian N6-DNA methyltransferase. The murine PRED28 encodes two alternatively spliced RNA. However, although recombinant PRED28 proteins are found in the nucleus, no evidence for an adenine-methyltransferase activity was detected.
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PMID:Undetectable levels of N6-methyl adenine in mouse DNA: Cloning and analysis of PRED28, a gene coding for a putative mammalian DNA adenine methyltransferase. 1668 35

While the Arabidopsis genome carries one copy of the methyltransferase 1 (MET1) gene for DNA methyltransferase, which is mainly responsible for maintaining CpG methylation, the rice genome bears two copies of the MET1 genes, OsMET1a and OsMET1b. The transcripts of OsMET1b accumulate more abundantly than those of OsMET1a in all of the tissues examined, and both genes actively transcribed at the callus, imbibed embryo, root, meristem, young panicle, anther, pistil, and endosperm, all of which contain actively dividing cells. The OsMET1a transcripts contain two 5'-untranslated exons and alternatively spliced 3'-terminal exons. The alternatively spliced transcripts consist of 14, 15, or 16 exons, and all of them encode a putative protein of 1527 amino acids. While the 3'-terminal exon of OsMET1b is unique, alternative splicing occurs in the 5'-terminal regions, which comprise either exons containing 5'-untranslated regions or an exon bearing the initiation codon. Depending upon alternative usage of 5' exons by alternative splicing, the OsMET1b transcripts comprise 11, 12, 13, or 14 exons, and the former two and the latter two longer transcripts encode putative proteins of 1486 and 1529 amino acids, respectively. Moreover, the 5' splicing patterns of OsMET1b can vary in different tissues. These findings are discussed with respect to the possible regulation of the OsMET1 genes.
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PMID:Alternative splicing of the rice OsMET1 genes encoding maintenance DNA methyltransferase. 1828 Nov 24

A major obstacle in human stem cell research is the limited number of reagents capable of distinguishing pluripotent stem cells from partially differentiated or incompletely reprogrammed derivatives. Although human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) express numerous alternatively spliced transcripts, little attention has been directed at developing splice variant-encoded protein isoforms as reagents for stem cell research. In this study, several genes encoding proteins involved in important signaling pathways were screened to detect alternatively spliced transcripts that exhibited differential expression in pluripotent stem cells (PSCs) relative to spontaneously differentiated cells (SDCs). Transcripts containing the alternatively spliced exon 10 of the de novo DNA methyltransferase gene, DNMT3B, were identified that are expressed in PSCs. To demonstrate the utility and superiority of splice variant specific reagents for stem cell research, a peptide encoded by DNMT3B exon 10 was used to generate an antibody, SG1. The SG1 antibody detects a single DNMT3B protein isoform that is expressed only in PSCs but not in SDCs. The SG1 antibody is also demonstrably superior to other antibodies at distinguishing PSCs from SDCs in mixed cultures containing both pluripotent stem cells and partially differentiated derivatives. The tightly controlled down regulation of DNMT3B exon 10 containing transcripts (and exon 10 encoded peptide) upon spontaneous differentiation of PSCs suggests that this DNMT3B splice isoform is characteristic of the pluripotent state. Alternatively spliced exons, and the proteins they encode, represent a vast untapped reservoir of novel biomarkers that can be used to develop superior reagents for stem cell research and to gain further insight into mechanisms controlling stem cell pluripotency.
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PMID:A DNMT3B alternatively spliced exon and encoded peptide are novel biomarkers of human pluripotent stem cells. 2169 79

DNA methyltransferase 3B (DNMT3B) is critical in abnormal DNA methylation patterns in cancer cells. Nearly 40 alternatively spliced variants of DNMT3B have been reported. DNMT3B4 and DNMT3B7 are two kinds of splice variants of DNMT3B lacking the conserved methyltransferase motif. In this study, the effect of inactivation of DNMT3B variants, DNMT3B4 and DNMT3B7, on cell proliferation was assessed. pCMV-DNMT3B4 and pCMV-DNMT3B7 recombinant plasmids were developed and stably transfected into 293A cells. 293A cells transfected with plasmid pCMV-DNMT3B4 or pCMV-2B were then treated with G418 to the stable cell lines. After that, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method was used for testing the proliferation level, and flow cytometry was used to test cell cycle distribution of the cell line. The expression of p21 was detected by real-time PCR and Western blot. The methylation status of p21 promoter was detected by methylation-specific PCR (MS-PCR). It was found that DNMT3B4 and DNMT3B7 overexpression could inhibit cell proliferation and increase the expression of p21. Cell cycle analysis demonstrated that inactivation of DNMT3B variants overexpression inhibited cell cycle progression. Inactivation of DNMT3B variants overexpression facilitated p21 expression to delay 293A cell proliferation. These findings indicate that inactivation of DNMT3B variants might play an important role in cell proliferation correlating with the change of p21.
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PMID:Splice variants DNMT3B4 and DNMT3B7 overexpression inhibit cell proliferation in 293A cell line. 2560 92

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