DNA-Topoisomerase II cleavage complex (TOP2cc)

The DNA-Topoisomerase II cleavage complex (TOP2cc) is a transient, covalent intermediate formed during the catalytic cycle of Topoisomerase II enzymes, which manage DNA topology by creating and resealing double-strand breaks [Nitiss, 2009, Nature Reviews Cancer]. These enzymes, specifically the TOP2A and TOP2B isoforms, are essential for resolving DNA knots, catenanes, and supercoiling that occur during replication and transcription [Pommier et al., 2010, Chemistry & Biology]. In rapidly dividing cells, such as those in malignant tumors, the TOP2A isoform is significantly upregulated to support the high demand for chromosome segregation and genomic stability during the cell cycle [UniProt P11388]. Therapeutic agents known as Topoisomerase II poisons, including etoposide and anthracyclines, specifically target this complex by trapping the enzyme in its DNA-bound state [StatPearls, 2023]. This stabilization prevents the re-ligation of the DNA strands, effectively converting the enzyme into a source of persistent, lethal double-strand breaks [PubMed: 19434091]. The resulting accumulation of DNA damage triggers apoptotic pathways, leading to the selective destruction of highly proliferative cancer cells [NIH/NCI Drug Dictionary]. However, the interaction of these drugs with the TOP2B isoform in non-dividing tissues is associated with severe adverse effects, most notably dose-dependent cardiotoxicity [Zhang et al., 2012, Nature Medicine]. Furthermore, the induction of DNA translocations at this complex can lead to the development of secondary malignancies, such as therapy-related acute myeloid leukemia [Cowell & Austin, 2012, Biochimica et Biophysica Acta].

Other names

Topoisomerase II-DNA complexTOP2-DNA cleavage complexCovalent Topoisomerase II-DNA intermediateTOP2cc

Stabilization of the covalent DNA-Topoisomerase II intermediate (cleavage complex), preventing DNA re-ligation and inducing lethal double-strand breaks.