DNA-Topoisomerase II complex (TOP2cc)

The DNA-Topoisomerase II complex, specifically the covalent cleavage complex (TOP2cc), is a critical transient intermediate formed during the catalytic cycle of topoisomerase II enzymes. These enzymes are essential for maintaining genomic integrity by resolving topological constraints such as supercoiling, knots, and catenanes that arise during DNA replication, transcription, and chromosome segregation [5, 14]. The enzyme functions by creating a temporary double-strand break in one DNA duplex to allow the passage of another duplex through the gate [11, 15]. In clinical oncology, this complex is the primary target for 'topoisomerase II poisons' like etoposide and doxorubicin, which trap the enzyme in its DNA-cleaved state [2, 8]. By preventing the religation of DNA, these drugs transform an essential cellular machine into a source of lethal double-strand breaks, effectively killing rapidly proliferating cancer cells [10, 18]. However, the persistence of these complexes can also lead to significant adverse effects, including cardiotoxicity and the risk of secondary leukemias due to chromosomal translocations [4, 11].

Other names

DNA and DNA–topoisomerase II complexTopoisomerase II-DNA cleavage complexTopoisomerase II-DNA covalent complexCleavable complexTop2-DNA complex

Topoisomerase II poisons act by stabilizing the transient covalent intermediate known as the cleavage complex (TOP2cc), which prevents the religation of the DNA strands. This stabilization converts the enzyme into a cellular toxin that generates permanent double-strand breaks when encountered by DNA tracking machineries like replication forks or transcription complexes, ultimately triggering programmed cell death (apoptosis) [1, 2, 8].