O6-Alkylguanine-DNA alkyltransferase: influence on susceptibility to the genetic effects of alkylating agents.

O6-Alkylguanine-DNA alkyltransferase (AGT) repairs DNA containing O6-alkylguanine by a suicide mechanism involving transfer of the alkyl group to its active site. In this way AGT protects cells from the mutagenic and cytotoxic effects of O6-alkylguanine-type lesions such as O6-methylguanine (O6-meG), an observation which has during recent years been confirmed by studies in transgenic animals either over-expressing or completely lacking this activity. While the levels of expression of AGT have been shown to affect strongly the repair of O6-meG after high doses of methylating agents inducing complete and prolonged depletion of the cellular AGT pool, other data suggest that within smaller variations of AGT levels (such as the interindividual variations observed in man or as observed after low or moderate exposures to alkylating agents) the dependence of O6-meG repair is limited. This phenomenon may reflect the intracellular distribution of the repair protein and must be taken into account when assessing the role of AGT in determining susceptibility to alkylating agents of environmental or clinical significance.