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Topoisomerase II inhibition involves characteristic chromosomal expression patterns

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE11942 | GEO | 2008/10/01

SECONDARY ACCESSION(S): PRJNA105795

REPOSITORIES: GEO

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Topoisomerase II inhibition involves characteristic chromosomal expression patterns.

Project description:BACKGROUND: The phenomenon of co-localization of transcriptionally upregulated genes showing similar expression levels is known across all eukaryotic genomes. We recently mapped the Aroclor 1254-regulated transcriptome back onto the genome and provided evidence for the statistically significant co-localization of regulated genes. They did, however, not always show similar expression levels, and many of the regulated genes were, in fact, repressed. RESULTS: In this study, we were able to reproduce this observation with microarray data stemming from 1) human hepatocytes treated with the gyrase and potential topoisomerase II inhibitor trovafloxacin, 2) human hepatocytes treated with the topoisomerase II inhibitor doxorubicin and 3) mouse lymphoma cells treated with the topoisomerase II inhibitor etoposide. We found statistically significant co-localization of regulated gene pairs--induced and repressed--within the window size of 0-100 kbp. Notably, by using microarray data stemming from lung tissue of a mouse transgenic line overexpressing the transcription factor c-myc, which served as a negative control, we found regulated genes to be located with regard to each other nearly in the same way as genes distributed randomly all over the genome (0-100 kbp). CONCLUSION: We suggest topoisomerase II inhibition by Aroclor 1254, trovafloxacin, doxorubicin, and etoposide to be responsible for significant co-localization of regulated genes through the inability of the stabilized enzyme complexes to religate DNA. Within the permanently opened chromatin domains, neighbored genes might be allowed to be regulated. Overexpression of c-myc, however, does not inhibit topoisomerase II activity. Consequently, the enzyme is able to perform its normal function of transiently breaking and rejoining the DNA double strand. As a result, exclusively target genes are regulated.

| S-EPMC2488358 | biostudies-literature

Topoisomerase II inhibition involves characteristic chromosomal expression patterns: Trovafloxacin study

Project description:Trovafloxacin is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. Specific members of this drug family display high activity against eukaryotic type II topoisomerase, as well as cultured mammalian cells and in vivo tumor models. Trovafloxacin seems to have a higher affinity for eukaryotic polymerase II system than the other quinolone agents tested. This effect coupled with other factors, such as an inflammatory response, might result in a hepatotoxic reaction seen with drug. In this study we found genes regulated by trovafloxacin - induced and repressed - to be located much closer to each other than genes distributed randomly all over the genome (< 100 kbp). Keywords: Trovafloxacin-treated human hepatocytes versus non-treated human hepatocytes

2008-10-01 | GSE11941 | GEO

Topoisomerase II inhibition involves characteristic chromosomal expression patterns: Doxorubicin study

Project description:A variety of important anticancer drugs kill cells by increasing cellular levels of topoisomerase II-DNA cleavage complex. The anthracycline anticancer drug doxorubicin forms a stable ternary complex with DNA and topoisomerase IIa, thereby inhibiting the normal function of the enzyme. In this study we found genes regulated by doxorubicin - induced and repressed - to be located much closer to each other than genes distributed randomly all over the genome (< 100 kbp). Keywords: Doxorubicin-treated human hepatocytes versus non-treated human hepatocytes

2008-10-01 | GSE11940 | GEO

Topoisomerase II inhibitors and histone eviction

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-06-04 | E-GEOD-33634 | biostudies-arrayexpress

Co-ordinate inhibition of autism candidate genes by topoisomerase inhibitors

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-08-30 | E-GEOD-43900 | biostudies-arrayexpress

Topoisomerase II inhibitors and histone eviction