Site-specific carcinogen binding to DNA in polytene chromosomes.

Kurth, Paul D.; Bustin, Michael

doi:10.1073/pnas.82.20.7076

Cited by 10 publications

(5 citation statements)

References 29 publications

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“…These include carcinogen specificity for certain bases within specific sequences [Hemminki, 1983;Wilkins, 1984Wilkins, , 1985Benasutti et al, 19881, sequence motifs [Kootstra et al, 19891, and preferential attack of linker vs. core DNA in nucleosomes 0 1994 Wiley-Liss, Inc. [Jack and Brookes, 1982;Kurian et al, 1985;Moyer et al, 19891, and unusual DNA structures such as Z-DNA [Marrot et al, 19871, replication forks [Paules et al, 19881, and other non-B-DNA structures [Kohwi-Shigematsu et al, 1988;Kohwi, 19891. Preferential DNA damage has also been demonstrated within "active" relative to "inactive" chromatin (as defined by differential DNase sensitivity) [Arrand and Murray, 1982;Delcuve et a]., 19881 or native RNA polymerase activity [Yu, 1983a,b], in repetitive relative to bulk DNA [Gupta, 19841, in ribosomal relative to total DNA [Irvin and Wogan, 19851, in matrix-associated relative to non-associated DNA [Obi et al, 19861, at chromosomal fragile sites [Yunis et al, 19871, and at specific chromosomal loci as determined by immunological techniques [Kurth and Bustin, 1985;Oliver0 et al, 19901. However, to date there is still little or no information regarding the distribution of chemically-induced DNA damage at the level of individual genes. The major impediment to examining targeting at this level is principally methodological.…”

Section: Ntro D Uctlo Nmentioning

confidence: 99%

Comparison of effects of direct‐acting DNA methylating and ethylating agents on inducible gene expression in vivo

McCaffrey

Hamilton

1994

Environ and Mol Mutagen

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Our laboratory is interested in whether chemical carcinogen-induced DNA damage is non-randomly distributed in the genome, i.e., "targeted," at the level of individual genes. As one means of investigating this, we have examined whether carcinogen treatment differentially alters the expression of specific genes in vivo. In this study, we have compared the effects of four direct-acting simple alkylating agents (methyl methanesulfonate, ethyl methanesulfonate, methylnitrosourea, and ethylnitrosourea) on the steady-state mRNA expression of a model inducible gene, phosphoenolpyruvate carboxykinase (PEPCK), using the chick embryo as a simple in vivo test system. We observed no effect of any of these four carcinogens on the steady-state mRNA expression of the constitutively expressed beta-actin, transferrin, or albumin genes in chick embryo liver following a single dose of carcinogen. In contrast, these same treatments significantly altered both the basal and inducible expression of the glucocorticoid-inducible PEPCK gene. These results support the hypothesis that inducible gene expression is a target for the effects of chemical carcinogens in vivo. In addition, the direction, magnitude, and time course of these effects were agent-specific. Qualitative and quantitative differences in effects between the methylating and ethylating agents and between the methanesulfonates and nitrosoureas were correlated with differences in their specific patterns of DNA adduct formation, suggesting that different DNA lesions have different effects on inducible gene expression.

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Section: Ntro D Uctlo Nmentioning

confidence: 99%

Comparison of effects of direct‐acting DNA methylating and ethylating agents on inducible gene expression in vivo

McCaffrey

Hamilton

1994

Environ and Mol Mutagen

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“…Several chemicals have also been demonstrated to preferentially attack linker versus core DNA in nucleosomes and unusual DNAstructuressuch asZ-DNA [ 1 I], replication forks [ 121, and other non-B-DNA structures [13,14]. At the highest levels of organization, preferential DNA damage has been demonstrated within "active" versus "inactive" chromatin (as defined by differential DNase sensitivity [ 1 5,161 or native RNA polymerase activity [ 17,18]), in repetitive versus bulk DNA [I 91, in ribosomal versus total DNA [20], in matrix-associated versus nonassociated DNA [21], at chromosomal fragile sites [221, and at specific chromosomal loci as determined by immunological techniques [23,24].…”

Section: Introductionmentioning

confidence: 99%

Preferential alteration of inducible gene expression in vivo by carcinogens that induce bulky DNA lesions

Hamilton¹,

Louis²,

Doherty³

et al. 1993

Molecular Carcinogenesis

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Our laboratory is interested in whether chemical carcinogen-induced DNA damage is nonrandomly distributed in the genome, i.e., "targeted," at the level of individual genes. To examine this, we have been investigating whether carcinogen treatment in vivo differentially alters the expression of specific genes. In this study, we examined the effects of four model carcinogens that induce bulky lesions in DNA--benzo[a]pyrene (B[a]P), aflatoxin B1 (AFB1), 7,12-dimethylbenz[a]anthracene (DMBA), and 2-acetylaminofluorene (AAF)--on the steady-state mRNA expression of several constitutive and drug-inducible genes in vivo. We specifically tested the hypothesis that carcinogen-induced DNA damage is preferentially targeted to inducible genes relative to constitutively expressed genes using the chick embryo as a simple in vivo test system. In summary, the four carcinogens had no effect on the steady-state mRNA expression of constitutively expressed beta-actin, transferrin, or albumin genes over a 24-h period after a single dose of each carcinogen. In contrast, each of these same treatments significantly altered the mRNA expression of two glutethimide-inducible genes, ALA synthase and CYP2H1. Both the basal expression of these genes and their drug-inducible expression was altered. B[a]P and AFB1 had similar effects on expression of the two inducible genes and caused similar levels of covalent adducts in total DNA, even though the administered doses differed by 30-fold. B[a]P binding to DNA, and the basal expression of CYP2H1 were similar in liver and lung. However, B[a]P significantly altered basal CYP2H1 mRNA expression in liver, a tissue in which this gene is highly inducible by glutethimide, and had no effect on basal CYP2H1 mRNA expression in lung, a tissue in which this gene is not drug-inducible. These data support the hypothesis that inducible gene expression is a target for carcinogen-induced DNA damage in vivo.

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“…Several chemicals including aflatoxin B 1 (AFB 1 ), benzo[a]pyrene (BaP), and 2-acetylaminofluorene (AAF) have also been demonstrated to preferentially attack linker vs. core DNA in nucleosomes (32)(33)(34), and unusual DNA structures such as Z-DNA (35), replication forks (36), and other non-B-DNA structures (37,38). At the highest levels of organization, preferential DNA damage has been demonstrated within "active" relative to "inactive" chromatin [as defined by differential DNase sensitivity (39,40) or native RNA polymerase activity (41,42)], in repetitive relative to bulk DNA (43), in ribosomal relative to total DNA (44), in matrix-associated relative to nonassociated DNA (45), at chromosomal fragile sites (46), and at specific chromosomal loci as determined by immunological techniques (47,48).…”

Section: Discussionmentioning

confidence: 99%

Developmentally specific effects of the DNA cross-linking agent mitomycin C on phosphoenolpyruvate carboxykinase gene expression in vivo: Correlation with changes in chromatin structure within the promoter region of the gene

Caron

Hamilton

1998

J. Biochem. Mol. Toxicol.

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Previous studies in our laboratory have demonstrated that genotoxic chemical carcinogens have strong preferential effects on expression of certain inducible genes at nonovertly toxic doses in vivo.The effects of the DNA cross-linking agent and chemotherapy drug, mitomycin C (MMC), on expression of the developmental and hormone-regulated gene, phosphoenolpyruvate carboxykinase (PEPCK), were examined in chick embryo liver in vivo as a function of development and were compared with changes in the chromatin structure of the PEPCK gene promoter. The liver PEPCK gene was fully hormone inducible as early as 8 days of embryonic development but was refractory to MMC until after day 10. This onset of responsiveness to MMC was correlated with qualitative changes in the pattern of DNase I hypersensitive sites (DHS) within the PEPCK promoter. There was also a gradual decrease and then a complete loss of both hormone inducibility and MMC responsiveness between 14 and 17 days of development that was correlated with a quantitative change in the overall DNase sensitivity of the liver PEPCK gene promoter over this period. These results suggest that carcinogen sensitivity of the PEPCK gene is related to its ability to respond to its normal induction signals and that chromatin structure may play a central role in these effects.

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Site-specific carcinogen binding to DNA in polytene chromosomes.

Cited by 10 publications

References 29 publications

Comparison of effects of direct‐acting DNA methylating and ethylating agents on inducible gene expression in vivo

Comparison of effects of direct‐acting DNA methylating and ethylating agents on inducible gene expression in vivo

Preferential alteration of inducible gene expression in vivo by carcinogens that induce bulky DNA lesions

Developmentally specific effects of the DNA cross-linking agent mitomycin C on phosphoenolpyruvate carboxykinase gene expression in vivo: Correlation with changes in chromatin structure within the promoter region of the gene

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