- slide 1 of 3
Why do Cells need DNA Methylation?
A cell contains only 1 or 2 sets of genomic DNA. Damaged proteins and RNA molecules can be effectively replaced using information set in the DNA. But DNA molecules themselves are unique and irreplaceable. Maintaining the integrity of the information in DNA is a cellular function supported by a complex set of DNA repair systems. DNA can become injured by a variety of processes, some impulsive, others catalyzed by environmental factors. Replication itself can occasionally damage the information content in DNA by leaving mispaired bases.
The chemistry of DNA damage is varied and intricate. The cellular retort to this damage includes a diverse range of enzymatic systems that catalyze some of the most fascinating chemical transformations in DNA metabolism.
During DNA replication, the base sequence of the newly formed DNA must be reproduced correctly, for even a single incorrect base could lead to lethal mutation. But with such vast number of bases, mistakes are inevitable.
When the enzyme, Pol III (a 3 prime -- 5 prime exonuclease) encounters, say, a G template strand, it is highly selective in that in the vast majority of cases, only dCTP is accepted into the active site of the enzyme and added to the nascent DNA chain and so on with other bases. In addition, Pol III also has a proofreading activity to ensure that the base pairings are correctly matched.
Despite the proofreading mechanism, to achieve fidelity of DNA replication, mistakes inevitably occur. One mechanism by which mistakes are prevented is called DNA methylation. It is a kind of chemical modification of DNA that remains stable over rounds of cell division and does not change the DNA sequence of an organism.
- slide 2 of 3
Origin of DNA Methylation
In prokaryotes, DNA methylation occurs at 5 prime region of the cytosine pyrimidine ring and the number 6 nitrogen of the adenine purine ring. However, in case of eukaryotes, DNA methylation occurs only at the 5th carbon of cytosine pyrimidine ring. And in mammalians, DNA methylation occurs at the 5th carbon of cytosine of CpG dinucleotide, however, there is only 1 percent of CpG present in human genome. Almost 70 to 80 percent of CpGs are methylated, however, unmethylated CpGs are found in clusters called CpG islands. It has been found that aberrant DNA methylation at the chromosomal regions known, as CpG islands are a crucial step in carcinogenesis.
In case of E.coli, wherever, there is a GATC sequence in the DNA, an enzyme called Dam methylase methylates the adenine of this sequence. This does not affect base pairing or DNA structure. It takes time after its synthesis for the new strand to be methylated and so for this brief period, it is unmethylated. Thus the parental strand is methylated but the new strand is not.
Mutations in of the DNA methylation machinery highlight several inherited syndromes such as immunodeficiency, centromere instability, facial abnormalities, and Rett syndrome, etc. There are other syndromes that are caused due to the disturbances in DNA methylation.
It is therefore, important for the cellular mechanism to work properly and DNA methylation is indeed one of the most important cellular machineries that ensure base pairing during DNA replication.