DNA topoisomerase 2-DNA cleavable complex (Topo II-DNA complex)

The DNA topoisomerase 2-DNA cleavable complex is a critical, transient intermediate formed during the catalytic cycle of topoisomerase II enzymes (TOP2A and TOP2B), where the enzyme creates a double-strand break and becomes covalently linked to the DNA backbone via a phosphotyrosyl bond (PubMed: 19455124). This complex is the specific target of 'topoisomerase II poisons,' such as etoposide and doxorubicin, which act by intercalating into the DNA or binding at the protein-DNA interface to prevent the re-ligation of the DNA strands (StatPearls: Topoisomerase Inhibitors). By stabilizing this normally short-lived complex, these drugs convert an essential enzyme into a potent cellular toxin that generates permanent double-strand breaks (PubMed: 12433371). The accumulation of these breaks overwhelms the cell's repair machinery, ultimately triggering apoptotic pathways, which is the basis for their use in treating various malignancies (UniProt: P11388). However, the formation of these complexes in non-cancerous cells is associated with significant clinical risks, including therapy-related leukemias and dose-limiting cardiotoxicity (PubMed: 21953124).

Other names

Topoisomerase II-DNA covalent complexTopo II-DNA cleavage complexTopoisomerase II-DNA adductTOP2-DNA complex

Stabilization of the covalent intermediate between DNA and topoisomerase II, preventing DNA re-ligation and inducing lethal double-strand breaks (PubMed: 19455124).