Topoisomerase II inhibition involves characteristic chromosomal expression patterns.
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).


CONCLUSIONS
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.
Reymann
Susanne
S
Fraunhofer Institute of Toxicology and Experimental Medicine (Fh-ITEM), Center for Drug Research and Medical Biotechnology, Nikolai-Fuchs-Str, 1, 30625 Hannover, Germany. reymann@item.fraunhofer.de
Borlak
Jürgen
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D008223:Lymphoma / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009287:Naphthyridines / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D009287:Naphthyridines; D016271:Proto-Oncogene Proteins c-myc; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D020111:Chlorodiphenyl (54% Chlorine); D005047:Etoposide; D004317:Doxorubicin; C080163:trovafloxacin