DNA methyltransferase
From Wikipedia, the free encyclopedia
In biochemistry, the DNA methyltransferase (DNA MTase) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.
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[edit] Classification
[edit] EC classification
MTases can be divided into three different groups on the basis of the chemical reactions they catalyze:
- m6A - those that generate N6-methyladenine EC 2.1.1.72
- m4C - those that generate N4-methylcytosine EC 2.1.1.113
- m5C - those that generate C5-methylcytosine EC 2.1.1.37
m6A and m4C methyltransferases are found primarily in prokaryotes. m5C methyltransfereases are found in some lower eukaryotes, in most higher plants, and in animals beginning with the echinoderms.
[edit] De novo and maintenance DNA MTases
De novo methyltransferases recognize something in the DNA that allows them to newly methylate cytosines. These are expressed mainly in early embryo development and they set up the pattern of methylation.
Maintenance methyltransferases add methylation to DNA when one strand is already methylated. These work throughout the life of the organism to maintain the methylation pattern that had been established by the de novo methyltransferases IS.
[edit] Mammalian DNA methyltransferase (DNMT)
Three active DNA methyltransferases have been identified in mammals. They are named DNMT1, DNMT3A and DNMT3B. A fourth enzyme previously known as DNMT2 is not a DNA methyltransferase (see below).
DNMT3L is a protein that is closely related to DNMT3A and DNMT3B structurally and that is critical for DNA methylation, but appears to be inactive on its own.
[edit] DNMT 1
DNMT1 is the most abundant DNA methyltransferase in mammalian cells, and considered to be the key maintenance methyltransferase in mammals. It predominantly methylates hemimethylated CpG di-nucleotides in the mammalian genome. This enzyme is 7–100 fold more active on hemimethylated DNA as compared with unmethylated substrate in vitro, but it is still more active at de novo methylation than other DNMTs. The recognition motif for the human enzyme involves only three of the bases in the CpG dinuclotide pair: a C on one strand and CpG on the other. This relaxed substrate specificity requirement allows it to methylate unusual structures like DNA slippage intermediates at de novo rates that equal its maintenance rate [1]. Like other DNA cytosine-5 methyltransferases the human enzyme recognizes flipped out cytosines in double stranded DNA and operates by the nucleophic attack mechanism [2]. In human cancer cells DNMT1 is responsible for both de novo and maintenance methylation of tumor suppressor genes [3][4].The enzyme is about 1620 amino acids long. The first 1100 amino acids constitute the regulatory domain of the enzyme, and the remaining residues constitute the catalytic domain. These are joined by Gly-Lys repeats. Both domains are required for the catalytic function of DNMT1.
DNMT1 has several isoforms, the somatic DNMT1, a splice variant (DNMT1b) and an oocyte specific isoform (DNMT1o). DNMT1o is synthesized and stored in the cytoplasm of the oocyte and translocated to the cell nucleus during early embryonic development, while the somatic DNMT1 is always found in the nucleus of somatic tissue.
DNMT1 null mutant embryonic stem cells were viable and contained a small percentage of methylated DNA and methyltransferase activity. Mouse embryos homozygous for a deletion in Dnmt1 die at 10-11 days gestation.[5]
[edit] TRDMT1 (formerly known as DNMT2)
Although this enzyme has strong sequence similarities with 5-methylcytosine methyltransferases of both prokaryotes and eukaryotes, in 2006 the enzyme was shown to methylate position 38 in Aspartic acid transfer RNA and does not methylate DNA. [6] To reflect this different function, the name for this methyltransferase has been changed to TRDMT1 (tRNA aspartic acid methyltransferase 1) to better reflect its biological function.[7] TRDMT1 is the first RNA cytosine methyltransferase to be identified in a human.
[edit] DNMT 3
DNMT3 is a family of DNA methyltransferases that could methylate hemimethylated and unmethylated CpG at the same rate. The architecture of DNMT3 enzymes is similar to DNMT1 with regulatory region attached to a catalytic domain. There are three known members of the DNMT3 family: DNMT3a, 3b and 3L.
DNMT3a and DNMT3b can mediate methylation-independent gene repression. DNMT3a can co-localize with heterochromatin protein (HP1 ) and methyl-CpG binding protein (MeCBP). They can also interact with DNMT1, which might be a co-operative event during DNA methylation. DNMT3a prefers CpG methylation to CpA, CpT, and CpC methylation, though there appears to be some sequence preference of methylation for DNMT3a and DNMT3b . DNMT3a methylates CpG sites at a rate much slower than DNMT1, but greater than DNMT3b.
DNMT3L contains DNA methyltransferase motifs and is required for establishing maternal genomic imprints, despite being catalytically inactive. DNMT3L is expressed during gametogenesis when genomic imprinting takes place. The loss of DNMT3L lead to bi-allelic expression of genes normally not expressed by the maternal allele. DNMT3L interacts with DNMT3a and DNMT3b and co-localized in the nucleus. Though DNMT3L appears incapable of methylation, it may participate in transcriptional repression.
[edit] See also
[edit] References
- ^ Mark R. Kho, David J.Baker, Ali Layoon, and Steven S. Smith (1998). "Stalling of Human DNA (Cytosine-5) Methyltransferase at Single Strand Conformers form a Site of Dynamic Mutation". Journal of Molecular Biology 275: 67-79. doi:.
- ^ Steven S. Smith, Bruce E. Kaplan, Lawrence C. Sowers and Edward M. Newman (1992). "Mechanism of Human Methyl-directed DNA methyltransferase and the Fidelity of Cytosine Methylation". Proceedings of the National Academy of Science, U.S.A. 89: 4748-4744. PMID 1584813.
- ^ Kam-Wing Jair, Kurtis E. Bachman, Hiromu Suzuki, Angela H.Ting, Ina Rhee, Ray-Whay Chiu Yen, Stephen B. Baylin and Kornel E. Schuebel (2006). "De novo CpG Island Methylation in Human Cancer Cells". Cancer Research 69: 682-692. PMID 16423997.
- ^ Angela H. Ting, Kam-wing Jair, Kornel E. Schuebel and Stephen B. Baylin (2006). "Differential Requirement for DNA Methyltransferse 1 In Maintianing Cancer Cell Gene Promoter Hypermethylation". Cancer Research 66: 729-735. PMID 16424002.
- ^ En Li, Timothy H. Bestor, and Rudolf Jaenisch (1992). "Targeted Mutation of the DNA Methyltransferase Gene Results in Embryonic Lethality". Cell 69: 915–926. doi:.
- ^ M.G. Goll, F. Kirpekar, K.A. Maggert, J.A. Yoder, C-L. Hsieh, X. Zhang, K.G. Golic, S.E. Jacobsen, T.H. Bestor (2006). "Methylation of tRNAAsp by the DNA Methyltransferase Homolog Dnmt2". Science 311 (5759): 395–398. doi:. PMID 16424344. [1]
- ^ [TRDMT1 tRNA aspartic acid methyltransferase 1 (Homo sapiens) http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1787]
- S S Smith (1994). Biological Implications of the Mechanism of Action of Human DNA (Cytosine-5) Methyltransferase Progress in Nucleic Acids Research and Molecular Biology 49: 65–111. [2]
- S Pradhan & PO Esteve (2003). Mammalian DNA (cytosine-5) methyltransferases and their expression. Clinical Immunology 109: 6–16. [3]
- MG Goll and TH Bestor (2005). Eukaryotic cytosine methyltransferase. Annual Review of Biochemistry 74: 481–514 [4]
[edit] External links
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Wikimedia Commons has media related to: Polymerase chain reaction |
- Information about DNA methyltransferases and DNA methylation at epigeneticstation.com
- Data for a DNA methyltransferase (DNMT) Antibody
- MeSH DNA+Modification+Methyltransferases
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