3-6.2.5 Modification of bases

Bases may be modified endogenously by normal cellular molecules. For example DNA may be methylated by S-adenosylmethionine (SAM) and glycosylated by reducing sugars.

Many compounds, such as PAHs, aromatic amines, aflatoxin and pyrrolizidine alkaloids, may form reactive oxygen species (ROS) catalyzed by cytochrome P450. These metabolites form adducts with the DNA, which can cause errors in replication, and thus bulky aromatic adducts may form stable intercalation between bases and block replication. The adducts may also induce conformational changes in the DNA. Some adducts also result in the depurination of the DNA, however it may vary how significant such depurination is in generating mutation.

Alkylation and arylation of bases can cause errors in replication. Some alkylating agents such as N-Nitrosamines may require the catalytic reaction of cytochrome-P450 for the formation of a reactive alkyl cation. N7 and O6 of guanine and the N3 and N7 of adenine are most susceptible to attack. N7 of guanine adducts form the bulk of DNA adducts, but they appear to be non-mutagenic. Alkylation at O6 of guanine however is harmful because excision repair of O6-adduct of guanine may be poor in some tissues such as the brain. The O6 methylation of guanine can result in G to A transition, while O4-methylthymine can be mis-paired with guanine. The type of the mutation generated however may be dependent on the size and type of the adduct as well as the DNA sequence. Ionizing radiations and reactive oxygen species often oxidize guanine to produce 8-oxoguanine.

3-6.2.6 Cross linking of DNA

Some alkylating agents produce cross linking of DNA. Some natural occurring chemicals such as psoralens after activation by UV radiation, and nitrous acid may also promote cross linking. Inter-strand cross-linking is more lethal as it blocks replication and transcription and can cause chromosomal breakages and rearrangements. Some cross linkers such as cyclophosphamide, mitomycin C and cisplatin are used as anticancer agent because of their high degree of toxicity to proliferating cells.

3-6.2.7 Dimerization

UV radiation promotes the formation of a cyclobutyl ring between adjacent thymines, resulting in the formation of pyrimidine dimers. In human skin cells, thousands of dimers may be formed in a day due to normal exposure to sunlight. Human DNA polymerase kappa help bypass these lesions in an error-free manner however, individuals with defective DNA repair function, such as sufferers of Xeroderma pigmentosum (autosomal recessive genetic disorder), are sensitive to sunlight and may be prone to skin cancer.