DNA methyltransferase

During DNA methylation, certain enzymes, the DNA methyltransferases (DMT), transfer a methyl group to defined cytosine molecules of the DNA double strand. Methylation takes place primarily at so-called CpG dinucleotides (CpG stands for cytosine-phosphatidyl-guanine). CG pairs located at the beginning of a gene are methylated particularly frequently. Methylation at this position usually prevents transcription of the gene by the RNA polymerase. DNA methylation is an important mechanism for regulating gene expression. It is also an important molecular biological, epigenetic tool. DNA methylation does not cause a genetic mutation, but only a modification of the gene. DNA methylation occurs in many living organisms and has various biological functions. The sequence of DNA methylation is based on the corresponding pattern of the parent cell and is then part of the epigenetic code of a cell.

The methyl-cleaving enzyme DNA demethylase has also been identified. The methylation of DNA is therefore not a one-way street, but the methylation state can be regulated depending on cell function. The methyl-binding protein (MeCP) can attach itself to methylated DNA. This process is in turn the starting point for further protein attachments, which lead to the modification of histones and ultimately to the inactivation of a chromosome segment.

So far, 3 human DNA methyltransferases are known:

• DNMT1
• DNMT3a and
• DNMT3b (Note: DNMT2 methylated RNA).

Maintenance methylation: DNMT1 is responsible for maintenance methylation during cell division. During DNA duplication before each cell division, certain nucleotides of the old DNA strand are methylated. However, the newly formed DNA strand is not yet methylated. This difference is compensated by DNMT1.

New methylation (de novo methylation): The methyltransferases DNMT3a and DNMT3b methylate the CG-dimers, which are remethylated due to cell differentiation (de novo methylation). New methylation is particularly common in the early stages of mammalian embryonic development.

Unmethylated cytidines are susceptible to deamination. In this process the amino group at position 4 of the ring is removed from the cytidines. A deaminated non-methylated cytidine is an uracil. This is not one of the 4 physiological DNA bases "adenine, cytosine, guanine or thymine". Therefore an uracil in the DNA is recognized as a defect and eliminated.

If a 5-methylcytidine is deaminated, thymine is formed. Thymine is a DNA building block. This means that the DNA repair system does not recognize whether this thymine or the opposite guanine was inserted incorrectly. The error is not recognized. The thymine is not eliminated. If this methylation has taken place in a germ cell, this mutation is also inherited.

DNA methylation and epigenetics: A number of environmental factors such as stress, smoking (influence on histone acetylation), various drugs(glucocorticoids, theophylline) can change the methylation pattern of a person, so that certain genes are activated while others are inactivated. Epigenetic mechanisms play a role in tumour development, e.g. by silencing tumour suppressor genes. In allergological diseases, connections between environmental pollution and DNA methylation behaviour are assumed.

1. Head JA (2014) Patterns of DNA methylation in animals: an ecotoxicological perspective. Integr Comp Biol 54:77-86.
2. Jeltsch A et al (2014) New concepts in DNA methylation. Trends Biochem Sci 39:310-318.
3. Moore LD et al (2013) DNA methylation and its basic function. Neuropsychopharmacology 38:23-38.