Molecular mechanisms of adaptive response to alkylating agents in Escherichia coli and some remarks on O(6)-methylguanine DNA-methyltransferase in other organisms.
Alkylating agents are environmental genotoxic agents with mutagenic and carcinogenic potential, however, their properties are also exploited in the treatment of malignant diseases. O(6)-Methylguanine is an important adduct formed by methylating agents that, if not repaired, can lead to mutations and death. Its repair is carried out by O(6)-methylguanine DNA-methyltransferase (MTase) in an unique reaction in which methyl groups are transferred to the cysteine acceptor site of the protein itself. Exposure of Escherichia coli cells to sublethal concentrations of methylating agents triggers the expression of a set of genes, which allows the cells to tolerate DNA lesions, and this kind of inducible repair is called the adaptive response. The MTase of E. coli, encoded by the ada gene was the first MTase to be discovered and one of best characterised. Its repair and regulatory mechanisms are understood in considerable detail and this bacterial protein played a key role in identification of its counterparts in other living organisms. This review summarises the nature of alkylation damage in DNA and our current knowledge about the adaptive response in E. coli. I also include a brief mention of MTases from other organisms with the emphasis on the human MTase, which could play a crucial role in both cancer prevention and cancer treatment.
Kleibl
Karol
K
Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91, Bratislava 37, Slovak Republic. exonklei@savba.sk
D000222:Adaptation, Physiological; D000477:Alkylating Agents / Q000494:pharmacology*; D000478:Alkylation; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000502:physiology; D004249:DNA Damage; D004269:DNA, Bacterial / Q000187:drug effects / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000502:physiology*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006801:Humans; D008322:Mammals / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000502:physiology*; D011387:Prokaryotic Cells / Q000201:enzymology; D013014:SOS Response, Genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology; D014157:Transcription Factors
D000477:Alkylating Agents; D018906:Antineoplastic Agents, Alkylating; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C045675:Ada protein, E coli; D019853:O(6)-Methylguanine-DNA Methyltransferase