Genetic and biochemical characterization of the CHO-UV-1 mutant defective in postreplication recovery of DNA

Cancer Res. 1990 Apr 15;50(8):2356-62.

Abstract

The CHO-UV-1 mutant, a Chinese hamster ovary cell with defective postreplication recovery of DNA, is 2- to 4-fold more sensitive than its wild-type counterpart (CHO-77256) to the lethal effects of ethylating agents and UV radiation; it is also hypersensitive (10- to 20-fold) to some DNA-methylating and -cross-linking agents. We studied the CHO-UV-1 mutant further to define its phenotype in terms of DNA damage induction and repair, methyltransferase activity, and effects of caffeine on mutational and lethal responses. Both wild-type and CHO-UV-1 cells incurred similar levels and types of damage when exposed to UV radiation, N-methyl-N'-nitro-N-nitrosoguanidine, or N-methyl-N-nitrosourea. The rate and extent of repair of Micrococcus luteus endonuclease-sensitive sites after UV irradiation or treatment with N-methyl-N'-nitro-N-nitrosoguanidine were also equivalent in these two cell types. Twenty % of the initial endonuclease-sensitive sites induced in either cell line remained at 18 h after UV irradiation; approximately 8% of the sites after N-methyl-N'-nitro-N-nitrosoguanidine exposure were present in both parental and CHO-UV-1 cells after a 17-h repair period. Moreover, the ability of CHO-UV-1 to resynthesize and ligate DNA during excision repair was similar to that of its parent. Neither CHO-UV-1 nor CHO-77256 had appreciable levels of O6-methylguanine-DNA methyltransferase activity which ameliorates the cytotoxicity of alkylating agents. Caffeine, a known inhibitor of postreplication repair, decreased the frequency of mutation induction at the hypoxanthine-guanine phosphoribosyltransferase locus by 40-55% in CHO-77256 but not in CHO-UV-1. These results rule out defective excision repair as a factor in the hypersensitivity of the CHO-UV-1 mutant to DNA-damaging agents. Hence, this cell line appears to derive from a mutation affecting nonexcision repair processes and should be useful in clarifying the mechanism(s) of postreplication recovery of DNA in mammalian cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Caffeine / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Cricetinae
  • Cricetulus
  • DNA / drug effects
  • DNA / radiation effects*
  • DNA Damage*
  • DNA Replication*
  • Ethyl Methanesulfonate / pharmacology*
  • Female
  • Hypoxanthine Phosphoribosyltransferase / genetics
  • Kinetics
  • Methylnitrosourea / pharmacology*
  • Mutation*
  • Ovary
  • Ultraviolet Rays*

Substances

  • Caffeine
  • Methylnitrosourea
  • DNA
  • Ethyl Methanesulfonate
  • Hypoxanthine Phosphoribosyltransferase