LACK OF PHENOTYPIC ALTERATION OF HMURA-DNA GLYCOSYLASE-DEFICIENT HAMSTER-CELLS EXPOSED TO DNA-DAMAGING AGENTS

V79mut1 cells are resistant to the toxic effects of 5-hydroxymethyl-2' -deoxyuridine (hmdUrd) and are deficient in the DNA repair enzyme hydr oxymethyluracil-DNA glycosylase (hmUDG). We have therefore proposed th at the toxicity of hmdUrd results from the repair of the lesion from D NA. In order to clarify the biological role of hmUDG, we have determin ed whether the repair-deficient cells showed resistance or sensitivity to the toxic or mutagenic effects of other DNA-damaging agents. Cells were exposed to hmdUrd, ionizing or ultraviolet radiation, to the alk ylating agent MNNG, and to oxidative stress produced by hypoxanthine/x anthine oxidase, glucose/glucose oxidase, nitric oxide donor SNAP, or to H2O2. The V79mut1 cells did not show increased mutagenesis in respo nse to hmdUrd. Relative to the V79 parent cells, the V79mut1 cells wer e not markedly altered in sensitivity to oxidizing agents and ionizing radiation (which produce hmdUra in DNA), The repair-deficient cells w ere equally sensitive as the parent V79 cells to DNA damage induced by ultraviolet radiation or by MNNG. No significant differences were see n between the parent and the repair-deficient cells in terms of synthe sis of poly(ADP-ribose) in response to damage or in their sensitizatio n to 3-aminobenzamide. Thus, the loss of the 5-hydroxymethyluracil (hm Ura)-DNA glycosylase activity in mammalian cells in culture confers no obvious deleterious effect on cell survival or mutagenicity in respon se to a wide range of DNA damage. These studies indicate that the majo r lesion known to be repaired by hmUra-DNA glycosylase, an hmUra resid ue replacing thymine, is produced in cells only in small quantities as the result of exposure to common DNA-damaging agents. These results r aise the possibility that hmUra-DNA glycosylase may have evolved to re spond to other lesions than hmUra residues formed from the oxidation o f thymine.