O6-Alkylguanine Alkytransferase

Alkylating reagents cause damage to DNA similar to that induced by ultraviolet irradiation in that various modified DNA bases are formed, some of which are lethal if not repaired and some of which are mutagenic. Three methylating or ethylating reagents are shown here.

The bases altered by these reagents are primarily purines (phosphate oxygens are also targets), and the spectrum of products formed varies with the reagent used. The most highly mutagenic of these products, O6-alkylguanine, is mutagenic because the modified base has a very high probability of pairing with thymine when the modified strand replicates (Figure 25.11). Thus, alkylation of a DNA-guanine stimulates a GC ---> AT transition.

Repair of this type of damage involves an unusual enzyme, O 6-alkylguanine alkyltransferase, which transfers a methyl or ethyl group from an O6-methylguanine or O6-ethylguanine residue to a cysteine residue in the active site of the protein. Thus, O 6-alkylguanine alkyltransferase (like photoreactivation) directly changes damaged bases rather than removing them then replacing them.

Remarkably, O 6-alkylguanine alkyltransferase is a catalyst that can function only once. Having become alkylated, it cannot remove the alkyl group, and the protein molecule turns over. Thus, this compound is not really an enzyme after all.

In bacteria O 6-alkylguanine alkyltransferase regulates both its own transcription and that of another repair enzyme, a DNA-N-glycosylase. There is evidence that the alkylated form of the alkyltransferase is the specific form of the transcriptional activator. This allows the cell to adapt to alkylation damage by using the alkylated protein as a specific signal to produce more of the proteins needed to repair the damage.

See also: Types and Consequences of DNA Damage, Photoreactivation

INTERNET LINK: DNA Repair