Metnase mediates resistance to topoisomerase II inhibitors in breast cancer cells

Justin Wray, Elizabeth A. Williamson, Melanie Royce, Montaser Shaheen, Brian D. Beck, Suk Hee Lee, Jac A. Nickoloff, Robert Hromas

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

DNA replication produces tangled, or catenated, chromatids, that must be decatenated prior to mitosis or catastrophic genomic damage will occur. Topoisomerase IIα (Topo IIα) is the primary decatenating enzyme. Cells monitor catenation status and activate decatenation checkpoints when decatenation is incomplete, which occurs when Topo IIα is inhibited by chemotherapy agents such as the anthracyclines and epididophyllotoxins. We recently demonstrated that the DNA repair component Metnase (also called SETMAR) enhances Topo IIα-mediated decatenation, and hypothesized that Metnase could mediate resistance to Topo IIα inhibitors. Here we show that Metnase interacts with Topo IIα in breast cancer cells, and that reducing Metnase expression significantly increases metaphase decatenation checkpoint arrest. Repression of Metnase sensitizes breast cancer cells to Topo IIα inhibitors, and directly blocks the inhibitory effect of the anthracycline adriamycin on Topo IIα-mediated decatenation in vitro. Thus, Metnase may mediate resistance to Topo IIα inhibitors, and could be a biomarker for clinical sensitivity to anthracyclines. Metnase could also become an important target for combination chemotherapy with current Topo IIα inhibitors, specifically in anthracycline-resistant breast cancer.

Original languageEnglish (US)
Article numbere5323
JournalPLoS ONE
Volume4
Issue number4
DOIs
StatePublished - Apr 24 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Wray, J., Williamson, E. A., Royce, M., Shaheen, M., Beck, B. D., Lee, S. H., Nickoloff, J. A., & Hromas, R. (2009). Metnase mediates resistance to topoisomerase II inhibitors in breast cancer cells. PLoS ONE, 4(4), [e5323]. https://doi.org/10.1371/journal.pone.0005323