DNA topoisomerase 2-alpha–DNA cleavage complex (TOP2A–DNA CC)

DNA topoisomerase 2-alpha (TOP2A) is an essential nuclear enzyme that manages DNA topology by generating transient double-strand breaks to allow the passage of one DNA helix through another (UniProt P11388). The Topoisomerase IIα–DNA cleavage complex represents the catalytic intermediate where the enzyme is covalently linked to the 5' ends of the broken DNA strands (Nitiss, 2009, Nature Reviews Cancer). This complex is the primary target for a class of chemotherapy drugs known as topoisomerase II poisons, such as etoposide and doxorubicin (PubChem). These agents act by stabilizing the cleavage complex, preventing the religation of the DNA strands and leading to the accumulation of permanent double-strand breaks. The resulting genomic instability triggers apoptotic pathways, making this target highly effective for treating various cancers where TOP2A is overexpressed (StatPearls, 2023). However, the stabilization of these complexes in healthy cells can lead to severe adverse effects, including therapy-related leukemias and cardiotoxicity (Pommier et al., 2016, Nature Reviews Drug Discovery).

Other names

Topoisomerase II alpha-DNA covalent complexTOP2A-DNA complexTopo II alpha-DNA cleavage complexTOP2A-DNA phosphotyrosyl complex

Stabilization of the covalent intermediate (cleavage complex) between the TOP2A enzyme and DNA, which inhibits the religation of the DNA phosphodiester backbone and converts the enzyme into a cellular toxin that induces double-strand breaks.