Regulation and expression of the adaptive response to alkylating agents

T. Lindahl, B. Sedgwick, M. Sekiguchi, Y. Nakabeppu

研究成果: ジャーナルへの寄稿評論記事

580 引用 (Scopus)

抄録

Inducible DNA repair pathways enable cells to display increased resistance to the deleterious effects of chemical mutagens and radiation. Several such networks have been delineated recently in Escherichia coli, including the SOS response, the adaptive response to alkylating agents, and inducible responses to oxygen radical damage in DNA. These various circuits are generally under positive regulatory control, but the biochemical strategies employed to generate specific protein activators differ between the pathways. In the adaptive response to alkylating agents, bacteria acquire increased resistance to the mutagenic and cell-killing effects of a large group of chemical mutagens. Alkylating agents, of which methylating agents appear to be widespread environmental mutagens, act through covalent modification of the cellular genome to generate miscoding base derivatives and lesions that block DNA replication. All oxygens and nitrogens in DNA can be modified by methylating agents, except for the nitrogens forming a glycosyl bond with deoxyribose, oxygens in phosphodiester bonds, and the exocyclic amino groups, resulting in 14 different types of primary lesions. However, the most relevant adducts are O6-methylguanine, which is a miscoding base, and 3-methyladenine, which is a cell-killing lesion. The main function of the adaptive response is to improve the repair of these two harmful base derivatives. To remove 3-methyladenine, cells employ the same strategy as for excision of anomalous bases such as uracil from DNA. The base-sugar bond is cleaved by a DNA glycosylase to release the altered base residue in free form and generate a repairable apurinic/apyrimidinic (AP) site. In contrast, O6-methylguanine is corrected by direct reversal of damage, accomplished by transfer of the methyl group to a cysteine residue in the repair enzyme itself. The protein is not regenerated and undergoes suicide inactivation as a consequence of the DNA repair event. The strategies for repair of these two important DNA lesions have been conserved during evolution. Thus, similar repair functions for these damaged purine residues are present in mammalian cells, although the responsible enzymes appear to be constitutively rather than inducibly expressed in higher cells. The same situation seems to hold true for the key component of the bacterial SOS response, the RecA protein: similar proteins that promote DNA strand transfer have been found in mammalian cells, but there is no evidence for their inducibility. Methylating agents trigger the adaptive response in E. coli by generating an intracellular signal for its induction. This signal has been identified recently as one of the minor DNA methylation products, one of the two stereoisomers of a methyl phosphotriester. The regulatory Ada protein transfers this particular methyl group to one of its own cysteine residues in a self-methylation reaction analogous to that employed for repair of O6-methylguanine, and this posttranslational modification event converts the protein from a weak to a strong transcriptional activator. The methylated protein binds tightly to a specific DNA sequence in the promoter regions of genes induced in the response, and thereby facilitates the initiation of transcription. Models of transcriptional activation by posttranslational modification of preexisting regulatory proteins have been proposed recently for several other systems.

元の言語英語
ページ(範囲)133-157
ページ数25
ジャーナルAnnual Review of Biochemistry
57
DOI
出版物ステータス出版済み - 1 1 1988

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Alkylating Agents
Repair
DNA
Mutagens
Proteins
Post Translational Protein Processing
DNA Repair
Cysteine
Escherichia coli
Nitrogen
Rec A Recombinases
DNA Glycosylases
Oxygen
Deoxyribose
Genes
Cells
Stereoisomerism
Derivatives
Uracil
DNA Methylation

All Science Journal Classification (ASJC) codes

  • Biochemistry

これを引用

Regulation and expression of the adaptive response to alkylating agents. / Lindahl, T.; Sedgwick, B.; Sekiguchi, M.; Nakabeppu, Y.

:: Annual Review of Biochemistry, 巻 57, 01.01.1988, p. 133-157.

研究成果: ジャーナルへの寄稿評論記事

Lindahl, T. ; Sedgwick, B. ; Sekiguchi, M. ; Nakabeppu, Y. / Regulation and expression of the adaptive response to alkylating agents. :: Annual Review of Biochemistry. 1988 ; 巻 57. pp. 133-157.
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