Complex Mechanisms of Topoisomerase II Poisons Revealed by Whole-genome Analysis

The potentially toxic nature of these DNA breaks made the drugs that stabilize them, TOP2 poisons, into highly successful anticancer agents, and research tools. However, despite decades-long widespread usage of these drugs, not much is known about differences in the genome-wide profiles of DNA breaks caused by them.

Here, we generated high-resolution genome-wide maps of DNA breaks induced by seven different TOP2 poisons in a human cancer cell line using the SSiNGLe method developed by our group. We found multiple notable differences even between the drugs with highly similar chemical structures, indicating that each poison targets a specific subpopulation of catalytically engaged TOP2 enzymes bound to DNA. The preferential targeting observed may be partly explained by the distinct local sequence preferences we identified for each TOP2 poison.