DNA topoisomerase II–DNA cleavage complex (Top2cc)

The DNA topoisomerase II–DNA cleavage complex (Top2cc) is a transient, covalent intermediate formed during the catalytic cycle of type II topoisomerases. In this state, the enzyme creates a double-strand break in DNA to allow another duplex to pass through, resolving topological constraints like supercoiling and catenation (UniProt P11388). While these complexes are normally short-lived, they are the specific molecular target for topoisomerase II poisons, a major class of anticancer agents (Nature Reviews Cancer, 2009). Drugs such as etoposide and doxorubicin bind to the Top2cc, preventing the religation of the DNA strands and effectively trapping the enzyme on the DNA (Biochemistry, 2013). This stabilization converts the essential enzyme into a potent cellular toxin by creating persistent double-strand breaks. The resulting genomic damage activates apoptotic pathways, leading to the death of rapidly dividing cancer cells. However, the formation of Top2cc at non-intended genomic sites can lead to chromosomal translocations, which are linked to the development of secondary malignancies like acute myeloid leukemia (StatPearls, 2023). Additionally, the presence of Top2cc in non-dividing cells, such as cardiomyocytes, contributes to the dose-limiting cardiotoxicity observed with anthracycline therapy.

Other names

Topoisomerase II-DNA covalent complexTop2 cleavage complexTOP2-DNA CCTopoisomerase II-DNA adduct

Stabilization of the transient covalent intermediate between the topoisomerase II enzyme and DNA, preventing the religation of the DNA phosphodiester backbone and converting the enzyme into a cellular toxin that induces permanent double-strand breaks (Nature Reviews Cancer, 2009; Biochemistry, 2013).