DNA demethylation is a process of removal of methyl group from nucleotide in DNA

DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

. DNA demethylation

Demethylation

Demethylation is the chemical process resulting in the removal a of methyl group from a molecule.A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms....

 could be passive and active. Passive process takes place in the absence of methylation of newly synthesised

Chemical synthesis

In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...

 DNA strands by DNMT1

DNMT1

DNA -methyltransferase 1 is an enzyme that in humans is encoded by the DNMT1 gene.-Interactions:DNMT1 has been shown to interact with Histone deacetylase 2, DMAP1, PCNA, Retinoblastoma protein, DNMT3A and DNMT3B.-Further reading:...

 during several replication rounds (for example, upon 5-Azacytidine

5-Azacytidine

Azacitidine or 5-azacytidine, sold under the trade name Vidaza, is a chemical analogue of cytidine, a nucleoside present in DNA and RNA. Azacitidine and its deoxy derivative, decitabine , are used in the treatment of myelodysplastic syndrome...

 treatment). Active DNA demethylation occurs via active dismiss of methyl group.

Examples of active DNA demethylation

All the cases of DNA demethylation could be divided on global (genome

Genome

In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

 wide) and specific (when just specific sequences are demethylated).
The genome wide DNA demethylation occurs:

1. In mammals:
   1. In male pronucleus
      Pronucleus
      A pronucleus is the nucleus of a sperm or an egg cell during the process of fertilization, after the sperm enters the ovum, but before they fuse. Sperm and egg cells are haploid, meaning they carry half the number of chromosomes...
      
       of zygote
      Zygote
      A zygote , or zygocyte, is the initial cell formed when two gamete cells are joined by means of sexual reproduction. In multicellular organisms, it is the earliest developmental stage of the embryo...
      
       immediately after fertilization;
   2. Possibly in the primordial germ cells (PGCs) of 11.5-12.5 day old embryos;
2. Possibly in amphibia - during midblastula
   Midblastula
   In developmental biology, midblastula or midblastula transition is a stage during embryonic development in which zygotic gene transcription is activated. There are three major characteristics of pre-MBT embryos. Firstly, all of the embryonic cells undergo cell division at the same time...
   
    transition

Examples of specific DNA demethylation:

1. Gene imprinting
   Imprinting
   Imprinting may refer to:* Genomic imprinting , a mechanism of regulating gene expression* Imprinting , in psychology and ethology* Molecular imprinting, in polymer chemistry...
   
    during plant reproduction;
2. Electroconvulsive stimulation-induced demethylation of neurotrophic factor genes in dentate gyrus neurons in the mouse brain

Possible mechanisms of active DNA demethylation

There are several proposed hypothetical mechanisms of active DNA demethylation:

A Direct removal of 5-methylcytosine

1. Direct removal of methyl group. This process has quite low thermodynamic probability.
2. Removal of methylated bases (either by direct removal of methylcytosine, or through cytosine deamination followed by removal of thymine from thymine/guanosine mismatch), followed by insertion of unmethylated one using base excision repair
   Base excision repair
   In biochemistry and genetics, base excision repair is a cellular mechanism that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky...
   
    machinery (BER).
3. Removal of entire DNA patch and following filling it with new nucleotides by nucleotide excision repair
   Nucleotide excision repair
   Nucleotide excision repair is a DNA repair mechanism. DNA constantly requires repair due to damage that can occur to bases from a vast variety of sources including chemicals, radiation and other mutagens...
   
    (NER).

B Removal of 5-methylcytosine via further modified cytosine bases

Oxidation of the methyl group generates 5-Hydroxymethylcytosine

5-Hydroxymethylcytosine

5-Hydroxymethylcytosine is a DNA pyrimidine nitrogen base. It is formed from the DNA base cytosine by adding a methyl group and then a hydroxy group. It is important in epigenetics, because the hydroxymethyl group on the cytosine can possibly switch a gene on and off. It was first seen in...

. Several mechanisms have been proposed to mediate demethylation of 5-hydroxymethylcytosines. This base can be either deaminated by AID/Apobec enzymes to give 5-Hydroxymethyluracil. Alternatively, TET enzymes can further oxidize 5-hydroxymethylcytosine to 5-Formylcytosine and 5-Carboxylcytosine.

1. Both the deamination and the oxidation products have been shown to be repaired by TDG, a glycosylase which is involved in base excision repair. A base excision mediated demethylation mechanism would yield double strand breaks if it occurs on large scale in CpG islands.
2. The carboxyl and formyl groups of 5-Formylcytosine and 5-Carboxylcytosine could be enzymatically removed without excision of the base. Precedent for similar reactions is found in biosynthetic pathways.