Invited Editorial Article. First paragraph: "Type II topoisomerase (TOP2) poisons are widely used chemotherapeutics that work by disrupting the cycle of TOP2-DNA interactions that are required for DNA synthesis, gene expression, and the maintenance of genome integrity. Schellenberg et al.’s recent Science paper, entitled “ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA protein cross-links” provides a major advancement in the understanding of the mechanisms that regulate TOP2-DNA interactions, and how they can inhibit the anticancer effects of TOP2 poisons. Through these new insights, promising new therapeutic targets have been identified."