DNA topoisomerase 2-alpha (TOP2A) – DNA cleavage complex (TOP2A-DNA CC)

The DNA topoisomerase 2-alpha (TOP2A) – DNA cleavage complex is a transient, covalent intermediate formed during the catalytic cycle of the enzyme DNA topoisomerase 2-alpha [3, 6]. In this state, the enzyme homodimer is covalently bonded to the 5' ends of a double-strand DNA break via phosphotyrosyl linkages, allowing the passage of another DNA duplex through the gate to resolve topological constraints such as supercoiling and catenanes [6, 10]. This complex is the specific pharmacological target of "topoisomerase II poisons," a class of potent anticancer drugs including etoposide and doxorubicin [3, 13]. These drugs stabilize the cleavage complex, preventing the religation of the DNA strands and effectively converting the enzyme into a cellular toxin that induces permanent double-strand breaks [11, 13]. The accumulation of these breaks triggers apoptotic pathways, leading to the death of rapidly proliferating cancer cells [11, 13]. However, the persistence of these complexes can also facilitate chromosomal translocations, such as those involving the MLL gene, which are associated with the development of secondary treatment-related leukemias [10, 11].

Other names

TOP2A-DNA cleavage complexTopoisomerase II alpha cleavable complexTOP2A-DNA covalent complexTopoisomerase II alpha-DNA adductTOP2A-DNA binary complexDNA topoisomerase II alpha-DNA cleavage complex

Stabilization of the covalent DNA-protein intermediate (cleavage complex) to prevent DNA religation, leading to double-strand breaks and apoptosis [3, 13].