DNA-Topoisomerase II alpha cleavable complex (TOP2Acc)

The DNA-Topoisomerase II alpha cleavable complex is a critical intermediate in the catalytic cycle of the Topoisomerase II alpha (TOP2A) enzyme, which manages DNA topology during essential cellular processes such as replication, transcription, and chromosome segregation [1, 5]. Under normal conditions, TOP2A creates transient double-strand breaks in DNA, passes another DNA duplex through the break, and then religates the strands [3]. However, certain chemotherapeutic agents, known as topoisomerase II poisons, act by stabilizing this covalent enzyme-DNA complex, effectively preventing the religation step [2]. This stabilization leads to the persistence of DNA breaks, which, when encountered by replication forks or transcription machinery, convert into permanent, lethal double-strand breaks [3]. The resulting genomic instability and DNA damage response typically trigger programmed cell death (apoptosis) in rapidly dividing cancer cells [1]. While highly effective in treating various malignancies, targeting this complex is associated with significant risks, including therapy-related secondary leukemias and cardiotoxicity, the latter often linked to off-target effects on the Topoisomerase II beta isoform [4].

Other names

Topoisomerase II alpha-DNA covalent complexTOP2A-DNA cleavage complexTOP2AccTopoisomerase II alpha-DNA complex

Topoisomerase II poisons stabilize the transient covalent intermediate (the cleavable complex) formed between the enzyme and DNA, preventing the religation of the DNA strands and leading to the accumulation of permanent double-strand breaks that trigger apoptosis [1, 2].