The heat shock transcription factor, HSF1, facilitates the catalytic engagement of topoisomerase IIb (TOP2B) within the neuronal genome

Topoisomerase II (TOP2) poisons, such as etoposide and doxorubicin, are potent antineoplastic drugs that are used to treat a variety of solid tumors and leukemias. Yet these drugs also cause significant secondary malignancies and toxicity to postmitotic cells. Proliferating mammalian cells express two TOP2 isoforms, TOP2A and TOP2B, while postmitotic cells only express TOP2B. Selectively targeting TOP2A, but not TOP2B, could thus prevent secondary toxicity in postmitotic cells, but such isoform-selective targeting strategies remain elusive. Here we report that the heat shock transcription factor, HSF1, facilitates the catalytic engagement of TOP2B on chromatin. Purified recombinant HSF1 stimulates the DNA cleavage and relaxation activity of purified TOP2B. Using atomic force microscopy, we show that HSF1 also enhances the recycling of TOP2B for subsequent rounds of DNA relaxation. TOP2B co-occupies the genome with HSF1 in both postmitotic and dividing cells, and either the knockdown or inhibition of HSF1 reduces the levels of catalytically engaged TOP2B. Intriguingly, HSF1 neither significantly interacts with TOP2A nor enhances its catalytic activity. Furthermore, pharmacological HSF1 inhibitors protect postmitotic cells from the cytotoxicity of TOP2 poisons without compromising their ability to kill cancer cells, revealing a potential strategy for minimizing the side-effects of TOP2 poison-based chemotherapy.