There are many different chemicals that directly chemically modify DNA. The methyl group (—CH3) can be added to DNA at various sites, two of which we will discuss further. There are several alkylation-sensitive sites in guanosine (identified in Table 3e). For example, methylation at the 7-position of the guanine base (Figure 4b) results in increased susceptibility of the deoxyribose–base bond to hydrolysis; 7-methyldeoxyguanosine is hydrolysed over 100 times more rapidly than is deoxyguanosine.
What is the consequence of this hydrolysis reaction?
The result will be an abasic site; in this case, loss of the guanine base.
Methylation at the O6 position of guanosine results in the formation of a modified nucleoside (O6-methylguanosine), shown in Table 3f. Unlike 7-methyldeoxyguanosine, 6-methyldeoxyguanosine is chemically stable. When this modification occurs, the normal G–C base pairing is disrupted by the presence of the methyl group at one of the hydrogen-bonding positions. (Look back to Figure 5a to confirm that this is so.) O6-methylguanine actually forms a more stable base-pair with thymine that it does with cytosine. If this modification occurs during DNA replication, mispairing with thymine can occur and, on subsequent replication steps, an A is placed opposite the T. Thus a G–C → A–T mutation occurs. There exists a unique repair enzyme for O6-methylguanosine, called O6-methylguanosine methyltransferase, which acts as a suicide protein, removing the methyl group but inactivating itself irreversibly.