Quantitative aspects of the repair of alkylated DNA in cultured mammalian cells

Roberts, J. J.; Pascoe, J M; Plant, Janet E.; Sturrock, J.E.; Crathorn, A. R.

doi:10.1016/0009-2797(71)90024-x

Cited by 124 publications

(14 citation statements)

References 16 publications

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“…Of the factors involved in the calculation of cryptogenic cell number, it seems probable that the sparing effect of split doses of HN2 and BCNU does represent the repair of alkylating damage to DNA. Such "repair synthesis" has been shown for mammalian cells in vitro, treated by drugs of all 3 classes of alkylating agent used in the present study (Roberts et al, 1971). However, we could not demonstrate recovery of cryptogenic cells between doses of IMS.…”

Section: Single Agentsupporting

confidence: 72%

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Ablation of murine jejunal crypts by alkylating agents

Moore¹

1979

Br J Cancer

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Summary.-The gut microcolony assay has been used to measure damage to intestinal crypts by single and split doses of 3 alkylating agents: mechlorethamine hydrochloride (HN2), bis-chloroethyl-nitrosourea (BCNU) and isopropyl methane sulphonate (IMS). The single-dose survival curves for whole crypts were distinguished by extrapolation numbers (3-0, 176 and 15 respectively) that were lower than most previously published values for assay by irradiation. Significant sparing of crypts occurred when doses of HN2 or BCNU, but not IMS, were given in 2 equal fractions separated by more than 2 h. Deduced Do values for those cells from which crypts regenerate were 1*9 mg/kg HN2, 19 mg/kg BCNU and 487 mg/kg IMS.

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Section: Single Agentsupporting

confidence: 72%

“…A test dose of 1000 rad of y-rays was given 6 h later. This interval was used because Roberts et al (1971) have shown for mammalian cells in vitro that repair of sublethal damage by alkylating agents should be largely complete by this time. The possibility of interaction between the 2 sets of damage may be thereby reduced.…”

Section: Methodsmentioning

confidence: 99%

Ablation of murine jejunal crypts by alkylating agents

Moore¹

1979

Br J Cancer

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“…The first position of the anticodon of several tRNA species from many organisms may contain a modified nucleoside (21). For example, queuine or hypoxanthine can be inserted into specific sites of certain tRNA species in ribosyl transfer reactions that displace free guanine from the precursor tRNA (22,23 (25,26). Inactivation of particular tRNA species is unlikely, on the grounds of target size, to be a major factor in the biological effects of methylating agents.…”

Section: Discussionmentioning

confidence: 99%

Possible depletion of a DNA repair enzyme in human lymphoma cells by subversive repair.

Karran¹

1985

Proc. Natl. Acad. Sci. U.S.A.

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Mex+ human lymphoma cell lines contain O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that undergoes suicide inactivation on interaction with its substrate. The cells are therefore competent to remove the alkylation lesion O6-methylguanine from their DNA. However, several repair-deficient lymphoma cell lines (Mex-) are also known. It is shown here that Mex+ cells can be converted temporarily to a Mex- phenotype by growth in nontoxic concentrations of free O6-methylguanine. The depletion of methyltransferase activity is not a result of O6-methylguanine incorporation into DNA and subsequent demethylation by the enzyme. It is proposed that O6-methylguanine is mistakenly incorporated into tRNA molecules by means of a post-transcriptional ribosyl transfer reaction. The demethylation of such bases in tRNA has been demonstrated by using bacterial and human DNA repair enzymes. The existence of such a subversive repair of a methylated base in tRNA raises the possibility of competition between DNA and RNA for cellular DNA repair enzymes. Furthermore, it is proposed that the known aberrant methylation of tRNA in certain transformed cells, together with subversive tRNA repair, could account for the Mex- phenotype.

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“…It is interesting that the toxicity of mustard is clearly related to its crosslinking capability, as monofunctional analogs are significantly less toxic (Pechura and Rall, 1993;Roberts et al, 1971;Nagy et al, 1945). Random alkylation of proteins could certainly destroy their natural function, but more subtle and far-reaching effects are possible through crosslinking.…”

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confidence: 99%

Mustard gas crosslinking of proteins through preferential alkylation of cysteines

1996

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Mustard gas, bis(2-chloroethyl)sulfide, treatment of proteins is shown to generate significant amounts of covalently crosslinked protein dimers. This is due to the preferential alkylation of cysteine residues. Crosslinking does not occur in the model protein staphylococcal nuclease, which has no cysteine residues. Treatment of cysteine-containing mutants of staphylococcal nuclease with this chemical warfare agent did result in crosslinking. However, these dimers are slowly cleaved back to monomers by an unknown mechanism. The alkylation and crosslinking of cysteine-containing proteins by mustard gas may contribute to its toxicity.

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Quantitative aspects of the repair of alkylated DNA in cultured mammalian cells

Cited by 124 publications

References 16 publications

Ablation of murine jejunal crypts by alkylating agents

Ablation of murine jejunal crypts by alkylating agents

Possible depletion of a DNA repair enzyme in human lymphoma cells by subversive repair.

Mustard gas crosslinking of proteins through preferential alkylation of cysteines

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