In L5178Y mouse lymphoblasts, ionizing radiation-induced mutant frequencies were dramatically higher when the genetic marker analyzed was heterozygous ($tk^{+}/tk^{-}$) than when hemizygous ($tk^{+}/tk^{0}$ or$hprt^{+}/hprt^{0}$). In contrast, base-change mutagens induced similar mutant frequencies at heterozygous and hemizygous loci. These results indicate that the majority of radiation-induced mutants harbor multilocus lesions, and that these mutants are poorly recovered when the target gene is in a hemizygous chromosomal region. Dose-rate dependence of radiation-induced mutant frequency was demonstrated at the heterozygous tk locus but not at the hemizygous hprt locus; in a cell line deficient in the rejoining of DNA double-strand breaks (DSBs), no dose-rate dependence was observed for either locus. The majority of${\rm TK}^{-/-}$ mutants, whether spontaneous or induced by X, α-particle or UV radiation, or by photosensitization, showed loss of the entire active tk allele. The percentage of${\rm TK}^{-/-}$ mutants exhibiting inactivation of galactokinase, encoded by the neighboring gk gene, was high in UV repair-deficient cells exposed to UV radiation and in DNA DSB repair-deficient lines exposed to X radiation. Thus the presence of unrepaired DNA lesions, whether DSBs or pyrimidine dimers, appears to result in an increase in the percentage of mutants harboring multilocus lesions.

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