FREQUENCY OF HPRT GENE-MUTATIONS INDUCED BY N-METHYL-N'-NITRO-N-NITROSOGUANIDINE CORRESPONDS TO REPLICATION ERROR PHENOTYPES OF CELL-LINES

We have examined whether cells with replication error-positive (RER+) and -negative phenotype (RER-) respond differently to the mutagen MNNG , employing three RER+ and two RER- human cell lines. Cells were treat ed with several concentrations of MNNG, and HPRT mutants were selected phenotypically by their growth in the presence of 6-thioguanine. Whil e the variation of the mutation frequency within each group was about an order of magnitude, it was found that MNNG induced a level of mutat ions in the HPRT gene some 100- to 1000-fold higher in RER+ cells than in cells with RER- phenotype. MNNG, at a concentration of 30 mu M, pr oduced a mutation frequency 450-fold higher in HCT116 (RER+) cells tha n in SW480 (RER-) cells. Our findings suggest that the RER+ phenotype predisposes cells to MNNG-induced hypermutability. (C) 1998 Elsevier S cience B.V.