Suppression of the radiation-sensitive phenotype of hamster irs1 and irs2 strains selected for resistance to 3-aminobenzamide.

PURPOSE:The radiosensitive hamster cell lines irs1 and irs2 have phenotypic similarities to cells defective in the early response to DNA-damaging agents as a result of mutations of the genes encoding poly(ADP-ribose)polymerase or ataxia-telangiectasia mutated (ATM). Whether modification of activity through selection of strains resistant to 3-aminobenzamide (3-AB) would affect the radiosensitive phenotype of irs1 and irs2 was examined. MATERIALS AND METHODS:3-AB-resistant strains of irs1, irs2 and their parent line V79 were established and their sensitivity to DNA-damaging agents was measured. In some 3-AB-resistant strains, the radiation resistance of DNA synthesis and the induction of apoptosis were also assayed. Additionally, a number of aspects of Pduanyu37 function were measured. RESULTS:Independently selected 3-AB-resistant strains of irs2 showed nearly complete suppression of radiation sensitivity, sensitivity to topoisomerase inhibitors, and radioresistant DNA synthesis. 3-AB-resistant strains of irs1 showed partial suppression of phenotype while 3-AB-resistant strains of V79 had no sensitivity changes. The induction of apoptosis in 3-AB-resistant strains of irs2 required substantially higher radiation doses than for irs2 itself. 3-AB-resistant strains had no detectable alteration of Pduanyu37 level or cleavage following ionizing irradiation and there were no mutations in the Pduanyu37 gene. CONCLUSIONS:Suppression of radiosensitivity associated with 3-AB resistance has important implications for mechanisms of tolerance to damage because it is able to override responses associated with specific genetic defects.

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