Methylation

Three types of natural methylation have been reported in DNA. Cytosine can be modified either on the ring to form 5-methylcytosine or on the exocyclic amino group to form N⁴-methylcytosine. Adenine may be modified to form N⁶-methyladenine. N⁴-methylcytosine and N⁶-methyladenine are found only in bacteria and archaea, whereas 5-methylcytosine is widely distributed. Special enzymes called DNA methyltransferases are responsible for this methylation; they recognize specific sequences within the DNA molecule so that only a subset of the bases is modified. Other methylations of the bases or of the deoxyribose are sometimes induced by carcinogens. These usually lead to mispairing of the bases during replication and have to be removed if they are not to become mutagenic.

Natural methylation has many cellular functions. In bacteria and archaea, methylation forms an essential part of the immune system by protecting DNA molecules from fragmentation by restriction endonucleases. In some organisms, methylation helps to eliminate incorrect base sequences introduced during DNA replication. By marking the parental strand with a methyl group, a cellular mechanism known as the mismatch repair system distinguishes between the newly replicated strand where the errors occur and the correct sequence on the template strand. In higher eukaryotes, 5-methylcytosine controls many cellular phenomena by preventing DNA transcription. Methylation is also believed to signal imprinting, a process whereby some genes inherited from one parent are selectively inactivated. Correct methylation may also repress or activate key genes that control embryonic development. On the other hand, 5-methylcytosine is potentially mutagenic because thymine produced during the methylation process converts C:G pairs to T:A pairs. In mammals, methylation takes place selectively within the dinucleotide sequence CG—a rare sequence, presumably because it has been lost by mutation. In many cancers, mutations are found in key genes at CG dinucleotides.