DNA topoisomerase II–DNA cleavage complex (Top2-cc) (Top2-cc)

The DNA topoisomerase II–DNA cleavage complex is a transient, covalent intermediate formed during the catalytic cycle of topoisomerase II enzymes, specifically the human isoforms TOP2A and TOP2B. These enzymes are essential for maintaining DNA topology by creating temporary double-strand breaks to resolve knots, tangles, and supercoils that arise during DNA replication, transcription, and chromosome segregation (Pommier et al., 2016, Nature Reviews Cancer). Under normal physiological conditions, the enzyme quickly religates the DNA strands after the topological change is complete. However, this complex is the specific pharmacological target of "topoisomerase poisons," such as etoposide, teniposide, and anthracyclines like doxorubicin (Deweese & Osheroff, 1999, Nucleic Acids Research). These drugs stabilize the cleavage complex, preventing DNA religation and transforming the enzyme into a source of persistent double-strand breaks. The accumulation of these breaks triggers the DNA damage response and leads to apoptosis, which is the basis for the clinical use of these agents in treating various cancers (Nitiss, 2009, Nature Reviews Cancer). Despite their efficacy, targeting this complex is associated with significant risks, including therapy-related secondary leukemias caused by illegitimate recombination and TOP2B-mediated cardiotoxicity (Zhang et al., 2012, Nature Medicine).

Other names

Topoisomerase II-DNA covalent complexTop2ccTop2-DNA complexTopoisomerase II-DNA intermediate

Stabilization of the transient covalent intermediate between the topoisomerase II enzyme and DNA, preventing the religation of the DNA strands and leading to the accumulation of permanent double-strand breaks.