Oxygens in DNA are main targets for ethylnitrosourea in normal and xeroderma pigmentosum fibroblasts and fetal rat brain cells

Singer, Brett C.; Bodell, William J.; Cleaver, James E.; Thomas, G. H.; Rajewsky, Manfred F.; Thon, W.

doi:10.1038/276085a0

Cited by 103 publications

(50 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another possibility is represented by the difficulty in digesting polymers with highly organized secondary structure-e.g., poly(dG)-poly-(dC) (18).…”

Section: Resultsmentioning

confidence: 99%

O4-Methyl, -ethyl, or -isopropyl substituents on thymidine in poly(dA-dT) all lead to transitions upon replication.

B¹,

Spengler²,

Fraenkel‐Conrat³

et al. 1986

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

View full text Add to dashboard Cite

In a previous paper, we reported that 04-methyl dTTP can be incorporated into poly(dA-dT) in place of thymidine without distortion of the helical structure, but on replication it could behave as deoxycytidine and misincorporate dGTP. Only weak interactions are possible for any O4-modified T A pair. While O"-alkyl TOG pairing should be favored, experiments to detect the ability of Escherichia coli DNA polymerase I (pol I) to utilize the triphosphate as dCTP were ambiguous. dTTPs with larger alkyl groups (ethyl, isopropyl) have now been synthesized and tested for their recognition as dTTP by pol I. Enhanced steric hindrance could be expected, particularly for 04-isopropyl dTTP, which has a three-carbon branched chain. However, both compounds behaved qualitatively like 04-methyl dTTP, being incorporated into poly(dA-dT) and then directing deoxyguanosine misincorporation by pol l. Quantitative comparisons of mutagenicity were not possible because of the finding that, unlike polymers made with 04-methyl dTTP, those made with ethyl or isopropyl dTTP were resistant to hydrolysis by using a variety of nucleases. The frequent misincorporations of dGTP would be expected to produce transitions in vivo. 04-ethyldeoxythymidine is very poorly repaired in vivo, which would also be expected for repair of 04-isopropyldeoxythymidine. Therefore, under suitable conditions, these particular carcinogen products are likely to be initiators of carcinogenesis.04-alkyldeoxythymidine, formed both in vitro and in vivo by N-nitroso methylating and ethylating agents (1) has been implicated in initiation of carcinogenesis (2, 3). Neither 04-methyldeoxythymidine (04-Me-dThd) nor 04-ethyldeoxythymidine (04-Et-dThd) is rapidly repaired in vivo (2-4), and the mechanism for their repair is not, at present, identified in mammals. It does not appear to be due to the 06-methyldeoxyguanosine methyltransferase, as is the case in bacteria (5). The analogous propylating agents are also carcinogenic (ref. 6 and refs. therein) and form both isopropyl and propyl bases (7,8). However, 04-isopropyl (or propyl) deoxythymidine (0"-iPr-dThd) has not been reported as a product; on the basis that 06-iPr-dGuo is formed in vivo (7) and that 04-butyldeoxythymidine has been identified in N-butyl-N-nitrosourea-treated DNA (9), it can be assumed that 04-iPr-dThd is also formed in vivo. Its repair would be expected to be even slower than repair of the methyl and ethyl analogues (2-7). Neither of the larger (ethyl, isopropyl) 0"-alkylthymidines has previously been investigated for potential mutagenicity and the ability to be utilized by polymerases, which would be indicative of carcinogenic potential.Both 04-Me-dThd and 04-methyl-and ethyluridine appear to simulate cytidine in transcription, replication, or codon-anticodon binding (10-13). 04-Methyl dTTP (04-MedTTP) could substitute for dTTP in primed poly(dA-dT) synthesis using Escherichia coli DNA polymerase I (pol I) (12). Upon copying such a polymer with the same enzyme, dGTP was incorporated, showing ag...

show abstract

“…Another possibility is represented by the difficulty in digesting polymers with highly organized secondary structure-e.g., poly(dG)-poly-(dC) (18).…”

Section: Resultsmentioning

confidence: 99%

O4-Methyl, -ethyl, or -isopropyl substituents on thymidine in poly(dA-dT) all lead to transitions upon replication.

B¹,

Spengler²,

Fraenkel‐Conrat³

et al. 1986

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

View full text Add to dashboard Cite

show abstract

“…The site of alkylation of a nucleic acid, in vivo or in vitro, is greatly dependent upon the type of alkylating agent (Jensen, 1978;Singer et al, 1978). In general, alkylating agents with low mutagenicity or carcinogenicity, such as dimethyl sulfate, are weak electrophiles and tend to attack primarily ring nitrogens.…”

Section: Enzymatic Methylation In Gene Expressionmentioning

confidence: 99%

5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

Nyce¹,

Weinhouse²,

Magee³

1983

Br J Cancer

View full text Add to dashboard Cite

Perhaps the most ubiquitous aspect of tumours and the neoplastic cells of which they are composed is their loss of the ability to control cellular functions in a normal way. During the development of the malignant state, the neoplastic cell becomes increasingly refractory to both the internal and external stimulae which integrate its normal counterparts into functional tissues and organ systems. This lack of integration is associated with alterations in the expression of a host of gene products, including, for example, the ectopic biosynthesis of hormones (

show abstract

“…BCNU is an S N 1 bifunctional alkylating agent that can form adducts at nucleophilic sites on DNA, including the O 6 position of Guanine (34)(35)(36). After this initial addition reaction, the alkyl group on O 6 of Guanine can react with the opposite Cytosine to form an interstrand cross-link; importantly, the O 6 alkyl group can be removed by a DNA repair protein known as O 6 -methylguanine DNA methyltransferase (MGMT) (37,38).…”

Section: Mgmt ؊/؊ Mice Display Sensitivity To Bcnu Exposure By the Inmentioning

confidence: 99%

In vitroerythropoiesis from bone marrow-derived progenitors provides a physiological assay for toxic and mutagenic compounds

Shuga

Zhang

Samson

et al. 2007

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

View full text Add to dashboard Cite

The goal of this study was to create an in vitro cell culture system that captures essential features of the in vivo erythroid micronucleus (MN) genotoxicity assay, thus enabling increased throughput and controlled studies of the hematopoietic DNA damage response. We show that adult bone marrow (BM) cultures respond to erythropoietin, the principal hormone that stimulates erythropoiesis, with physiological erythropoietic proliferation, differentiation, and enucleation. We then show that this in vitro erythropoietic system clearly signals exposure to genotoxicants through erythroid MN formation. Furthermore, we determined that DNA repair-deficient (MGMT ؊/؊ ) BM displayed sensitivity to genotoxic exposure in vivo compared with WT BM and that this phenotypic response was reflected in erythropoietic cultures. These findings suggest that this in vitro erythroid MN assay is capable of screening for genotoxicity on BM in a physiologically reflective manner. Finally, responses to genotoxicants during erythroid differentiation varied with exposure time, demonstrating that this system can be used to study the effect of DNA damage at specific developmental stages.in vitro toxicity screens ͉ genotoxicity ͉ hematopoiesis ͉ DNA damage and repair

show abstract

Oxygens in DNA are main targets for ethylnitrosourea in normal and xeroderma pigmentosum fibroblasts and fetal rat brain cells

Cited by 103 publications

References 16 publications

O4-Methyl, -ethyl, or -isopropyl substituents on thymidine in poly(dA-dT) all lead to transitions upon replication.

O4-Methyl, -ethyl, or -isopropyl substituents on thymidine in poly(dA-dT) all lead to transitions upon replication.

5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

In vitroerythropoiesis from bone marrow-derived progenitors provides a physiological assay for toxic and mutagenic compounds

Contact Info

Product

Resources

About