Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells

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