Bacterial assays for recombinagens

Hoffmann, George

doi:10.1016/0027-5107(92)90028-z

Cited by 14 publications

(12 citation statements)

References 125 publications

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“…This suggests that breakage and repair of D N A occur in a random manner. Some experiments also support this model of DNA cleavage by a random manner, in which X-ray irradiation, considered to be one of the risk factors of leukemias, induces chromosomal breakages scattered over entire chromosomes among X-ray-irradiated human lymphocytes (Roman et a]., 1973;Buckton et al, 1976), or strand exchanges in bacteriophages or plasmid DNA with scattered breakage points (Hoffmann, 1992).…”

Section: Discussionmentioning

confidence: 93%

“…In contrast to lymphoid malignancies, few studies have been performed on junctional sequences in acute myeloid leukemia (von Lindern et al., 1992;Negrini et al, 1993). We previously analyzed the breakpoints of the PML and RARA genes from 40 patients with APL by Southern blotting .…”

Section: Introductionmentioning

confidence: 97%

“…T h e breakpoints of the RARA gene are consistently localized within intron 2, and those of the PML gene are clustered in two regions separated by about 10 kb, mainly introns 3 and 6 (Pandolfi et al., 1992;Fukutani et al, 1993). T h e resultant PML-RARA fusion mRNA encodes a chimeric protein (Kakizuka et al, 1991; al., 1991) and is associated with leukemogenesis in APL (Grignani et al, 1993).…”

Section: Introductionmentioning

confidence: 98%

“…Sequence analysis of joining regions has presented several models concerning the mechanisms of chromosomal translocations (Croce et Chen et al, 1989;von Lindern et al., 1992;Negrini et al., 1993).…”

Section: Introductionmentioning

confidence: 98%

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Analysis of the joining sequences of the t(15;17) translocation in human acute promyelocytic leukemia: Sequence non‐specific recombination between the pml and rara genes within identical short stretches

Yoshida

Naoe

Fukutani

et al. 1995

Genes Chromosomes & Cancer

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Molecular analysis of the t(15;17) translocation in 70 patients with acute promyelocytic leukemia (APL) confirmed that the breakpoints of chromosome 15 were located in two regions of the promyelocytic leukemia (PML) gene, mainly introns 3 and 6, whereas the breakpoints of chromosome 17 were consistently in intron 2 of the retinoic acid receptor alpha (RARA) gene. To study the reason for the clustering of the breakpoints and the underlying mechanism of the chromosomal translocation, we characterized the joining sequences of der(15) and der (17) by polymerase chain reaction in samples from eight patients with APL. There was no cluster of the breakpoints within the introns, and no consensus sequence-motif was found around them. One or nine extra nucleotides were inserted into two joining sites. There were identical stretches of one to seven nucleotides between the PML and RARA genes in the majority of the joining sequences. These data provide a potential model of the t(15;17) translocation: random DNA double strand cleavage, modification of DNA ends by enzymes including terminal deoxynucleotidyl transferase, and single strand base-pairing within identical short stretches. Furthermore, APL develops only when the PML and RARA genes are rearranged, within restricted genomic regions and a functional PML-RARA chimeric product is produced, and this might lead to a clustering of the breakpoints.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

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Analysis of the joining sequences of the t(15;17) translocation in human acute promyelocytic leukemia: Sequence non‐specific recombination between the pml and rara genes within identical short stretches

Yoshida

Naoe

Fukutani

et al. 1995

Genes Chromosomes & Cancer

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“…In contrast to a large battery of test systems designed for the identifiation of mutagens, only few systems exist where recombinagens can be detected (8)(9)(10). One of these is based on the lower eukaryotic yeast Saccharomyces cerevisiae and uses strain D7 which has been constructed by Zimmermann and colleagues (11).…”

Section: Introductionmentioning

confidence: 99%

High promutagen activating capacity of yeast microsomes containing human cytochrome P-450 1A and human NADPH-cytochrome P-450 reductase

1994

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Yeast Saccharomyces cerevisiae strains have been constructed that co-express cDNAs coding for the human cytochrome P-450 enzymes CYP1A1 or CYP1A2 in combination with human NADPH-cytochrome P-450 reductase (oxidoreductase). Microsomal fractions prepared from the strains were able to efficiently activate various drugs to Salmonella mutagens. These experiments demonstrated that a functional interaction occurred between the respective human enzymes in the yeast microsomes. For every drug tested, the microsomes containing CYP enzymes and oxidoreductase were 2-to 4-fold better in activation than the corresponding microsomes that contained CYP alone. Interestingly, co-expression of CYP1A2 with oxidoreductase resulted in a decrease of 7-ethoxyresorufin-0-deethylase activity, a problem which is related to this specific substrate. Using the microsomes, it was demonstrated that aflatoxin B, was activated to a mutagen not only by CYP1A2 but also by CYP1A1. In contrast, benzo[a]pyrene was exclusively activated by CYP1A1 whereas CYP1A2 was inactive. The drug 3-amino-l-methyl-5//-pyrido[4,3-ft]indole (Trp-P-2) was activated by CYP1A2 and to a lesser extent by CYP1A1. A strong substrate specificity was observed with the two structurally related heterocyclic arylamines 2-amino-3,4-dimethyUmidazo[4,5-/]quinoUne (MelQ) and 2-amino-3,8-dimethyUmidazo[4,5-/]quinoxaline (MelQ*). MeIQ x was activated efficiently by both CYP enzymes, whereas MelQ was only activated by CYP1A2 and not by CYP1A1. The fact that microsomes from vector transformed control strains were unable to activate any of the drugs studied underlines the suitability of these microsomes for metabolic studies. Moreover, the presence of suitable marker genes in the yeast strains will enable us to study mitotic recombination and gene conversion events induced by drugs that require metabolic activation.

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Induction of genetic recombination: Consequences and model systems

Hoffmann¹

1994

Environ. Mol. Mutagen.

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Radiation and many chemicals have been found to induce homologous genetic recombination. Experimental systems that allow the detection and characterization of recombinagens exist in organisms as diverse as bacteria, fungi, plants, insects, and mammals. Recombination plays an important role in many biological processes, and studies of recombinagens can provide insight into underlying mechanisms. Studies of recombinagens are also of applied interest in genetic toxicology, because recombinational events in somatic cells can contribute to human disease. Clear connections have been established between mitotic recombination and the etiology of some cancers. This article briefly reviews two aspects of the induction of genetic recombination by radiation and chemicals--the health implications of recombinagenic effects and assays for detecting recombinagens.

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Bacterial assays for recombinagens

Cited by 14 publications

References 125 publications

Analysis of the joining sequences of the t(15;17) translocation in human acute promyelocytic leukemia: Sequence non‐specific recombination between the pml and rara genes within identical short stretches

Analysis of the joining sequences of the t(15;17) translocation in human acute promyelocytic leukemia: Sequence non‐specific recombination between the pml and rara genes within identical short stretches

High promutagen activating capacity of yeast microsomes containing human cytochrome P-450 1A and human NADPH-cytochrome P-450 reductase

Induction of genetic recombination: Consequences and model systems

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