DNA topoisomerase 2-DNA cleavage complex (Topo II-DCC) (Topo II-DCC)

The DNA topoisomerase 2-DNA cleavage complex is a transient, covalent intermediate formed during the catalytic cycle of topoisomerase II enzymes, specifically the TOP2A and TOP2B isoforms (Pommier, 2013, Nat Rev Drug Discov). These enzymes are essential for maintaining genomic integrity by creating temporary double-strand breaks that allow DNA strands to pass through one another, thereby resolving topological strain during replication and transcription (Nitiss, 2009, Nat Rev Cancer). Anthracyclines, such as doxorubicin and daunorubicin, act as "topoisomerase poisons" by intercalating into the DNA at the cleavage site and stabilizing this covalent complex (StatPearls, 2023, Anthracyclines). This stabilization prevents the religation of the DNA strands, effectively converting the enzyme into a source of lethal DNA double-strand breaks (Minotti et al., 2004, Pharmacol Rev). The resulting accumulation of DNA damage triggers apoptotic pathways, which is the primary mechanism for their anti-tumor efficacy. However, the interaction with the TOP2B isoform in non-dividing cells, particularly cardiomyocytes, is recognized as the molecular basis for the dose-limiting cardiotoxicity associated with anthracycline therapy (Zhang et al., 2012, Nat Med).

Other names

Topoisomerase II-DNA covalent complexTopo II-DNA cleavable complexTopoisomerase II-DNA adductAnthracycline-Topoisomerase II-DNA ternary complex

Anthracyclines act as topoisomerase II poisons by intercalating into DNA and stabilizing the covalent enzyme-DNA cleavage complex, preventing DNA religation and leading to double-strand breaks.