DNA topoisomerase II–DNA cleavable complex (TOP2-DNA CC) (TOP2-DNA CC)

The DNA topoisomerase II–DNA cleavable complex (TOP2cc) is a transient, covalent intermediate formed during the catalytic cycle of topoisomerase II enzymes (Nitiss, J. L., 2009, Nature Reviews Cancer). Under normal physiological conditions, topoisomerase II (TOP2) manages DNA supercoiling, tangling, and knotting by creating a temporary double-strand break, passing another DNA duplex through the gate, and then religating the broken strands (Pommier, Y., 2013, Nature Reviews Cancer). This process is vital for essential cellular activities such as DNA replication, transcription, and chromosome segregation during mitosis (UniProt P11388). However, certain chemotherapeutic agents, known as topoisomerase II poisons, specifically target this intermediate by binding to the enzyme-DNA interface and preventing the religation step (StatPearls, 2023). This stabilization of the TOP2cc transforms a necessary cellular tool into a lethal genomic lesion, leading to the accumulation of permanent double-strand breaks. If these breaks are not repaired, they trigger programmed cell death (apoptosis), making the TOP2cc a critical focal point for cancer therapy. While effective against rapidly dividing malignant cells, the persistence of these complexes can also lead to significant side effects, including cardiotoxicity and secondary leukemias, often due to off-target effects on the TOP2B isoform in non-cancerous tissues (Zhang, S. et al., 2012, Nature Medicine).

Other names

TOP2ccTopoisomerase II-DNA cleavage complexCovalent TOP2-DNA complexTOP2-DNA covalent complex

Stabilization of the covalent enzyme-DNA intermediate (cleavable complex), preventing DNA religation and converting transient breaks into permanent double-strand breaks that trigger apoptosis (Pommier, Y., 2013, Nature Reviews Cancer).