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Molecular and Cellular Biology, December 2001, p. 8437-8451, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8437-8451.2001

Transcriptional Consequences of Topoisomerase Inhibition

Irene Collins, Achim Weber,dagger and David Levens*

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-1500

Received 14 June 2001/Returned for modification 17 July 2001/Accepted 17 September 2001

In principle, the generation, transmission, and dissipation of supercoiling forces are determined by the arrangement of the physical barriers defining topological boundaries and the disposition of enzymes creating (polymerases and helicases, etc.) or releasing (topoisomerases) torsional strain in DNA. These features are likely to be characteristic for individual genes. By using topoisomerase inhibitors to alter the balance between supercoiling forces in vivo, we monitored changes in the basal transcriptional activity and DNA conformation for several genes. Every gene examined displayed an individualized profile in response to inhibition of topoisomerase I or II. The expression changes elicited by camptothecin (topoisomerase I inhibitor) or adriamycin (topoisomerase II inhibitor) were not equivalent. Camptothecin generally caused transcription complexes to stall in the midst of transcription units, while provoking little response at promoters. Adriamycin, in contrast, caused dramatic changes at or near promoters and prevented transcription. The response to topoisomerase inhibition was also context dependent, differing between chromosomal or episomal c-myc promoters. In addition to being well-characterized DNA-damaging agents, topoisomerase inhibitors may evoke a biological response determined in part from transcriptional effects. The results have ramifications for the use of these drugs as antineoplastic agents.

* Corresponding author. Mailing address: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bldg. 10, Rm. 2N106, Bethesda, MD 20892-1500. Phone: (301) 496-2176. Fax: (301) 594-5227. E-mail: levens{at}helix.nih.gov.

dagger Present address: Institute for Molecular Pathology, Eberhard-Karls-Universität, 72076 Tübingen, Germany.

Molecular and Cellular Biology, December 2001, p. 8437-8451, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8437-8451.2001


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