Induction of Enzymes Involved in DNA Repair and Mutagenesis

Abstract

Three phenomena examined here have been claimed to reflect the operation of inducible repair systems. It has been postulated that 'SOS repair' involves the induction by DNA-damaging agents of an error-prone repair system that is capable of affecting the replication of damaged DNA. This system works with bacteriophages and animal viruses, in which it is possible to separate the effects of DNA damage on the viral DNA from that on the host cell. Whether this system also operates in repair of the cell's own DNA is, however, controversial. The system appears to have little effect on survival of bacterial cells and its operation in cellular mutagenesis is still not proven, at least in bacteria with otherwise normal repair capacity. 'Adaptation' is the response of bacteria to low doses of methylating agents. Adapted bacteria are more resistant to the lethal and mutagenic action of alkytlating agents. The process includes the induction of an enzyme that 'removes' O6-alkylated bases from DNA and which, unusually, is consumed during the course of the reaction. The reaction itself is also unknown; it does not depend on a nuclease, glycosylase or demethylase, but could use a transmethylase. There is some evidence that an analogous process occurs in animals. The third process affects the synthesis of high molecular weight DNA in cultured mammalian cells that have been exposed to split doses of DNA-damaging agents. It has been postulated that this system is inducible and error-free, but detailed analysis suggests that the observed effect is an artifact arising from an abnormal distribution of sizes of nascent DNA after the second dose, and as a result of exposure to the first dose. Inducible DNA repair systems may be expected to influence kinetics of the dose--response relationships obtained after exposure of cells to mutagens and carcinogens. The interactions between these effects and those produced by inducible pathways of metabolic activation and detoxification are discussed.