PROPYLENE-OXIDE MUTAGENESIS AT TEMPLATE CYTOSINE RESIDUES

Propylene oxide (PO) is a widely used industrial reagent which is muta genic and carcinogenic. We have recently shown that a variety of aliph atic epoxides, including propylene oxide, can react with DNA to form h ydroxyalkyl adducts at N-3 of cytosine which rapidly undergo hydrolyti c deamination to produce uracil adducts. These 3-hydroxyalkyl uracil a dducts are stable in DNA and are postulated to be an important class o f potentially mutagenic lesions. Mutagenesis at cytosine residues due to PO modification of single-stranded M13mp2/C141 DNA was studied by t ransfection of modified DNA into SOS and non-SOS induced E. coli host cells. Mutations of the proline (CCC) codon at C141 which result in re version of the lacZ phenotype (blue plaques) were scored. It was found that PO treatment of single-stranded DNA results in dose-dependent mu tagenesis that is highly SOS dependent. The spectrum of base-substitut ion mutations found at this site differed when PO-modified DNA was tra nsfected into E. coli with different DNA repair backgrounds. These res ults indicate that propylene oxide induced DNA adducts at template cyt osine residues are mutagenic in E. coil and that this mutagenesis is g reatly increased by SOS processing. They also show that these lesions may be repaired by one Or more mechanisms. (C) 1994 Wiley-Liss, Inc.