Lesions alkylated bases

The abasic sites (3, Scheme 8.2) resulting from the loss of alkylated bases from DNA are both cytotoxic and mutagenic. " The cyclic acetal (3) exists in equilibrium with small amounts (—1%) of the open chain aldehyde (4). The acidic nature of a-proton in the aldehyde form of the abasic lesion facilitates 3-elimination of the 3 -phosphate residue to yield a strand break. " This reaction occurs with a half-life of about 200 h under physiological conditions (pH 7.4, 37°C), but can be accelerated by heat, basic conditions, or the presence of various amines. " ... 

So we are still left with two models of the stereochemistry of DNA alkylated by a PAH diol epoxide the PAH either lies in a groove of DNA or else tries to intercalate between the bass of DNA. Since it is covalently bonded to a base it must cause considerable distortion if it tries to lie between the bases. However, the stacking observed in the crystalline state seems to argue for partial intercalation. We will need crystal structures of at least one appropriately alkylated polynucleotide before this problem can be resolved. And when this is done it will be just the beginning of the answer to the problem of alkylation of DNA by activated carcinogens. The subsequent question is, what is the lesion in DNA that is important in carcinogenesis, and then what does it cause to happen so that tumor formation is initiated ... 

Based on these studies, it has been suggested that alkylation of nucleophilic sites, including SH-containing enzymes, is the underlying biochemical lesion responsible... 

A mitigating factor in this process are the various cellular DNA repair enzyme systems which may remove the chemically induced lesion before or after DNA replication. A number of these which actively repair damage as a result of short-chained alkylation, much as would be expected to occur as a result of exposure to the genotoxic pesticides methyl bromide or ethylene dibromide, are listed in Table 2. However, the activity of repair enzyme systems does represent a saturable process and in some instances may itself be the source of errors in DNA base sequences, possibly by an inducible error-prone DNA repair enzyme system analogous to the so-... 

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