Effects of aphidicolin on the repair and fixation of potentially lethal damage sensitive to beta-araA.

The effects of aphidicolin, a specific inhibitor of DNA polymerase alpha, on the repair and fixation of potentially lethal damage (PLD) sensitive to treatment with beta-araA--a drug acting via inhibition of DNA polymerases alpha and beta-have been studied. Three micrograms/ml of aphidicolin given after irradiation did not produce any significant modification in cell survival. More damage was nevertheless fixed by a given concentration of beta-araA in the presence of aphidicolin to a degree that 10 microM beta-araA given together with 3 micrograms/ml aphidicolin produced an effect similar to that of 70 microM beta-araA given alone. Although aphidicolin significantly enhanced the effectiveness of beta-araA in fixing PLD, it did not significantly increase the sector of lesions affected. Combined treatment with beta-araA and aphidicolin reduced or eliminated the shoulder from the survival curve without affecting the slope, an effect similar to that observed after treatment of cells with beta-araA alone. The presence of aphidicolin during the time interval trep allowed for repair of the beta-araA sensitive PLD resulted in a significant reduction in the repair rate. Based on these results, the necessity of distinction between inhibition of a repair process and fixation of the damage undergoing repair is discussed, as well as the possible involvement of DNA polymerase alpha and beta in the repair and fixation of the DNA damage that underlies repair of PLD.