DNA topoisomerase 2-DNA cleavage complex (TOP2cc)

DNA topoisomerase 2 (TOP2) is a critical nuclear enzyme that regulates DNA topology by generating transient double-strand breaks to allow the passage of one DNA duplex through another, a process essential for replication, transcription, and chromosome segregation [2, 4]. The DNA topoisomerase 2-DNA cleavage complex (TOP2cc) is the specific catalytic intermediate where the enzyme is covalently tethered to the 5' ends of the broken DNA [3, 19]. This complex is the primary pharmacological target for 'topoisomerase II poisons' such as etoposide and anthracyclines, which stabilize the TOP2cc and prevent DNA re-ligation [1, 16]. The resulting accumulation of protein-blocked DNA breaks is highly cytotoxic to rapidly dividing cancer cells, making it a cornerstone of various chemotherapy regimens [5, 11]. However, the stabilization of these complexes can also lead to chromosomal translocations and off-target effects, such as cardiotoxicity and secondary leukemias, particularly when the TOP2B isoform is involved [10, 17, 20].

Other names

Topoisomerase II-DNA covalent complexTopoisomerase II-cleavable complexTOP2-DNA complexDNA topoisomerase (ATP-hydrolyzing) cleavage complex

Topoisomerase II poisons stabilize the transient covalent intermediate formed between the enzyme and DNA (the cleavage complex), preventing the re-ligation of the double-strand break. This leads to the accumulation of permanent DNA breaks, which stall replication and transcription machinery, ultimately triggering programmed cell death (apoptosis).