Repair of O6-ethylguanine in DNA by a chromatin fraction from rat liver: transfer of the ethyl group to an acceptor protein.

Mehta, Jitendra R.; Ludlum, David B.; Renard, A.; Verly, Walter G.

doi:10.1073/pnas.78.11.6766

Cited by 67 publications

(23 citation statements)

References 23 publications

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“…AT reacts with DNA containing 06-alkylguanine residues and catalyzes the transfer of the alkyl group to a cysteine acceptor site contained within its protein sequence (8)(9)(10)(11)(12)(13)(14)(15)(16). This transfer restores the DNA structure to normal within a single step but the AT protein becomes stoichiometrically in- activated because the alkylcysteine is not regenerated rapidly if at all.…”

Section: Introductionmentioning

confidence: 99%

Studies of the repair of O6-alkylguanine and O4-alkylthymine in DNA by alkyltransferases from mammalian cells and bacteria.

Pegg¹,

Dolan²,

Scicchitano³

et al. 1985

Environ Health Perspect

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06-Methylguanine in DNA is repaired by the action of a protein termed 06-alkylguanine-DNA alkyltransferase (AT) which transfers the methyl group to a cysteine residue in its own sequence. Since the cysteine which is methylated is not regenerated rapidly, if at all, the capacity for repair of 06-methylguanine is limited by the number of molecules of the AT available within the cell. The level and inducibility of the AT differed greatly in different mammalian cell types and species with the highest levels in human tissues and in liver and the lowest levels in brain. Only a small induction occurred in rat liver in response to exposure to alkylating agents. In E. coli such exposure increased the activity more than 100-fold. The AT was not specific for methyl groups but also removed ethyl, 2-hydroxyethyl, n-propyl, isopropyl and nbutyl groups from the 06-position in DNA. The protein isolated from E. coli removed methyl groups much more rapidly than the larger alkyl groups but the mammalian AT isolated from rat liver showed much less difference in rate with adducts of different size. Ethyl and n-propyl groups were removed by the rat liver AT only three to four times more slowly than methyl groups. Another important difference between the bacterial and mammalian ATs is that the bacterial protein was also able to remove methyl groups from the 04-position of thymine in methylated DNA or poly(dT) but the AT from rat liver or human fibroblasts did not repair 04_methylthymidine. These results indicate that the results obtained with the E. coli system may not be a suitable model for extrapolation to predictions of the effects of alkylating agents in initiating tumors or mutations in mammalian cells.

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Section: Introductionmentioning

confidence: 99%

Studies of the repair of O6-alkylguanine and O4-alkylthymine in DNA by alkyltransferases from mammalian cells and bacteria.

Pegg¹,

Dolan²,

Scicchitano³

et al. 1985

Environ Health Perspect

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“…These alkylations are eliminated in prokaryotes and eukaryotes (Olsson and Lindahl, 1980;Mehta et al, 1981;Lindahl, 1976;Laval, 1977) through an o6 alkylguanine alkyltransferase (O6ATase) acting on o6 methylguanine (06-meGua) and a 3-methyladenine glycosylase (3-meAde gly) acting on a 3-methyladenine (3-meAde) and other alkylpurines.…”

mentioning

confidence: 99%

3-methyladenine-DNA-glycosylase and O6-alkyl guanine-DNA-alkyltransferase activities and sensitivity to alkylating agents in human cancer cell lines

Damia

Imperatori²,

Citti³

et al. 1996

Br J Cancer

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Summary The activities and the expression of 3-methyladenine glycosylase (3-meAde gly) and O6-alkylguanine-DNA-alkyltransferase (06ATase) were investigated in ten human cancer cell lines. Both 3-meAde gly and 06ATase activities were variable among different cell lines. mRNA levels of the 06ATase gene, appeared to be related to the content of 06ATase in different cell lines, whereas no apparent correlation was found between mRNA of 3-meAde gly and the enzymatic activity. No correlation was found between the activity of the two enzymes and the sensitivity to alkylating agents of different structures such as CC-1065, tallimustine, dimethylsulphate (DMSO), N-methyl-N'-nitro-N-ntirosoguanidine (MNNG), cis-diamminedichloroplatinum (cDDP) and melphalan (L-PAM). The most striking finding of this study is that a correlation exists between the activity of O6ATase and 3-meAde gly in the various cell lines investigated (P<0.01), suggesting a common mechanism of regulation of two DNA repair enzymes.

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“…The O6MeG adduct is lost from both bacterial and mammalian cells by a special reaction mechanism in which the methyl group of the O6MeG is transferred to the cysteine of an acceptor protein (3,21,24). As a result of this transfer, the acceptor protein is inactivated.…”

mentioning

confidence: 99%

Regulation of the capacity for O6-methylguanine removal from DNA in human lymphoblastoid cells studied by cell hybridization.

Ayres¹,

Sklar²,

K³

et al. 1982

Mol. Cell. Biol.

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Hybrids were made between a ouabain-resistant, thioguanine-resistant human lymphoma line able to remove O6-methylguanine from its DNA (Mex+) and human lymphoblastoid lines deficient in this capability (Mex-). The formation of hybrids was confirmed by chromosomal analysis. Hybrid cells had an O6-methylguanine removal capacity per mole of guanine about one third to one half that of the Mex+ parents, i.e., about the same per cell. Cell hybrids removed the same amount of the alkylation adduct 3-methyladenine as did their parents per mole of guanine, i.e., about twice as much per cell. Although the cell hybrids had intermediate resistance to the cytotoxic action of N-methyl-N'-nitro-N-nitrosoguanidine used to induce O6-methylguanine and 3-methyladenine, there is evidence that the ability to remove O6-methylguanine and resistance to the cytotoxic effect of N-methyl-N'-nitro-N-nitrosoguanidine are dissociable characteristics.

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Repair of O6-ethylguanine in DNA by a chromatin fraction from rat liver: transfer of the ethyl group to an acceptor protein.

Cited by 67 publications

References 23 publications

Studies of the repair of O6-alkylguanine and O4-alkylthymine in DNA by alkyltransferases from mammalian cells and bacteria.

Studies of the repair of O6-alkylguanine and O4-alkylthymine in DNA by alkyltransferases from mammalian cells and bacteria.

3-methyladenine-DNA-glycosylase and O6-alkyl guanine-DNA-alkyltransferase activities and sensitivity to alkylating agents in human cancer cell lines

Regulation of the capacity for O6-methylguanine removal from DNA in human lymphoblastoid cells studied by cell hybridization.

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