title: Involvement of separate pathways in the repair of mutational and lethal lesions induced by a monofunctional sulfur mustard.
abstract: The mutagenic and lethal effects of a monofunctional sulfur mustard, 2-chloro-ethylethylsulfide (CEES), have been studied in a number of repair deficient variants of Escherichia coli K12, B/r and B. The results indicate that CEES induces a (pre)mutational lesion which is subject to Uvr+-excision-repair. Extensive CEES-induced mutagenesis can occur in exrA- uvrA- and recA- uvrB- variants suggesting that the majority of the mutations in Uvr-bacteria do not arise from error-prone repair. These findings are similar to results previously reported with a volatile degradation product of captan and with ethyl methanesulfonate (EMS) but differ from those reported with methyl methanesulfonate (MMS). It is hypothesized that CEES alkylates guanine at the O-6 position (R-O-6-G) and that this R-O-6-G which is Uvr+-excisable is directly mutagenic by producing G-C to A-T transitions during replication. Reduced levels of induced mutation frequencies observed in an endonuclease II-deficient variant lead us to postulate that, in constrast to Uvr- bacteria, CEES-induced mutation in wild-type cells arise from error-prone repair of apurinic sites. Analysis of the lethal actions of CEES indicates that the lesion produced is largely unexcisable by the Uvr+ system. Host-cell reactivation of CEES-treated TI bacteriophage shows that the production of the (pre)ethal lesion is dependent on both the initial dose and post-treatment incubation. The efficient repair of the (pre)ethal lesion requires both endonuclease II and polymerase I. Moreover, deficiencies of these two enzymes rendered bacteria more sensitive to the cytotoxic action of CEES. It is postulated that the lethal mechanism of CEES involves: (I) alkylation at the N-3 position of adenine and the N-7 position of guanine; (2) spontaneous depurination of these alkylated bases; and (3) production of apurinic sites which are lethal unless repaired by the endonuclease II-polymerase I excision-repair system.
mesh_terms: D000225:Adenine / Q000378:metabolism; D000478:Alkylation; D002470:Cell Survival; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D004269:DNA, Bacterial / Q000096:biosynthesis; D004720:Endonucleases / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D006147:Guanine / Q000378:metabolism; D008698:Mesylates / Q000494:pharmacology; D009150:Mustard Compounds / Q000494:pharmacology*; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation
chemical_list: D004269:DNA, Bacterial; D008698:Mesylates; D009150:Mustard Compounds; D009153:Mutagens; D006147:Guanine; D004254:DNA Nucleotidyltransferases; D004720:Endonucleases; D000225:Adenine