DNA methyltransferase

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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Classification

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

De novo and maintenance DNA MTases

De novo methyltransferases recognize something in the DNA that allows them to methylate cytosines de novo. 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.

Mammalian DNA methyltransferase (DNMT)

Four active DNA methyltransferases have been identified in mammals. They are named DNMT1, DNMT2 (TRDMT1), DNMT3A and DNMT3B.

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.

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 7–20 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 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.^[1]

DNMT 2

Although DNMT2 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. ^[2] 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.^[3] TRDMT1 is the first RNA cytosine methyltransferase to be identified in a vertebrate.^{[citation needed]}

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.

See also

• Methyltransferase
• DNA methylation
• PRMT4 pathway

References

1. ^ En Li, Timothy H. Bestor, and Rudolf Jaenisch (1992). "Targeted Mutation of the DNA Methyltransferase Gene Results in Embryonic Lethality". Cell 69: 915-926.
2. ^ 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 tRNA^Asp by the DNA Methyltransferase Homolog Dnmt2". Science 311 (5759): 395-398. [1]
3. ^ [TRDMT1 tRNA aspartic acid methyltransferase 1 (Homo sapiens) http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1787]

• S Pradhan & PO Esteve (2003). Mammalian DNA (cytosine-5) methyltransferases and their expression. Clinical Immunology 109: 6–16. [2]
• MG Goll and TH Bestor (2005). Eukaryotic cytosine methyltransferase. Annual Review of Biochemistry 74: 481–514 [3]