title: Induction of the adaptive response of Escherichia coli to alkylation damage by the environmental mutagen, methyl chloride.
abstract: Methyl chloride (MeCl) is an abundant environmental mutagen and carcinogen and may be one of several environmental alkylating agents against which the protection of an adaptive response is required in microorganisms. Both MeCl and methyl iodide (MeI), at micromolar concentrations, induced the adaptive response to alkylation damage in Escherichia coli. This response is regulated by the Ada protein which is converted into a transcriptional activator by self-methylation on repair of methylphosphotriesters in methylated DNA. However, using high amounts of Ada protein, activation of Ada occurred in vitro following direct protein methylation by both MeI (in agreement with previously published data) and MeCl. Activation was enhanced when methyl halide treatments were performed in the presence of DNA. An unadapted E. coli cell contains only 2 to 4 molecules of Ada protein, and presents an extremely small target of 2 to 4 specific cysteine residues per cell for activation of Ada by direct protein methylation in vivo. Thus, it is proposed that induction of the adaptive response in vivo initially occurs via efficient repair by the Ada protein of a low number of methylphosphotriesters in DNA. When the cellular Ada protein level has substantially increased, a greater probability of direct methylation and activation of Ada at cysteine-69 by MeCl may sustain and further increase induction of the adaptive response.
authors.affiliation: Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Potters Bar, Herts, UK.
authors.forename: P
authors.initials: P
authors.lastname: Vaughan
authors.forename: T
authors.initials: T
authors.lastname: Lindahl
authors.forename: B
authors.initials: B
authors.lastname: Sedgwick
mesh_terms: D000222:Adaptation, Physiological; D000477:Alkylating Agents / Q000494:pharmacology*; D000478:Alkylation; D001426:Bacterial Proteins / Q000235:genetics; D004249:DNA Damage; D004269:DNA, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D029968:Escherichia coli Proteins; D015964:Gene Expression Regulation, Bacterial; D006847:Hydrocarbons, Iodinated / Q000494:pharmacology; D008737:Methyl Chloride / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000477:Alkylating Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D006847:Hydrocarbons, Iodinated; D014157:Transcription Factors; D008737:Methyl Chloride; C014055:methyl iodide; C045675:Ada protein, E coli; D019853:O(6)-Methylguanine-DNA Methyltransferase