DNA–topoisomerase II cleavable complex (Top2cc)

The DNA–topoisomerase II cleavable complex is a transient catalytic intermediate formed during the action of topoisomerase II (TOP2) enzymes, which manage DNA topology by creating and resealing double-strand breaks [12, 16]. In this state, the enzyme is covalently bonded to the 5' phosphate ends of the DNA through a tyrosyl-phosphodiester linkage, allowing another DNA duplex to pass through the gate [12, 13]. While essential for processes like DNA replication, transcription, and chromosome segregation, this complex is the primary target for a class of anticancer agents known as topoisomerase II poisons [1, 14]. Drugs such as etoposide and doxorubicin act by stabilizing this complex, preventing the religation of the DNA strands and effectively converting the enzyme into a cellular toxin that induces permanent double-strand breaks [1, 12]. The resulting accumulation of DNA damage triggers apoptotic pathways, making it a potent strategy for treating various malignancies [10, 16]. However, the persistence of these complexes can also lead to genomic instability and secondary cancers, such as treatment-related acute myeloid leukemia (t-AML) involving MLL gene translocations, and cardiotoxicity linked to the TOP2B isoform [8, 9, 11].

Other names

Topoisomerase II-DNA covalent complexTopo II-DNA complexCleavable complexTop2-DNA covalent complexTop2cc

Stabilization of the transient covalent intermediate (cleavable complex) between topoisomerase II and DNA, preventing the religation of the DNA double-strand break and leading to the accumulation of permanent DNA damage and subsequent apoptosis.