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

DNA topoisomerase 2-alpha (TOP2A) is a vital nuclear enzyme that regulates DNA supercoiling and removes knots or tangles by creating transient double-strand breaks (UniProt P11388). The TOP2A-DNA cleavage complex is the specific catalytic intermediate where the enzyme is covalently linked to the DNA backbone via a phosphotyrosyl bond (Nature Reviews Cancer, 2009). This complex is the primary pharmacological target for 'topoisomerase poisons,' such as etoposide and anthracyclines, which stabilize the complex and prevent DNA religation (Nature Reviews Cancer, 2013). By trapping these complexes, drugs convert an essential enzyme into a potent inducer of genomic instability, leading to permanent double-strand breaks and programmed cell death (Nucleic Acids Research, 2009). This mechanism is highly effective in rapidly dividing cancer cells, making the complex a cornerstone target in the treatment of various solid tumors and hematological malignancies (StatPearls, 2023). However, the stabilization of these complexes can also lead to off-target DNA damage in healthy cells, contributing to serious side effects like secondary leukemias and cardiotoxicity (Journal of Biological Chemistry, 2014).

Other names

Topoisomerase II alpha-DNA covalent complexTOP2A-DNA phosphotyrosyl complexTOP2A-DNA cleavage intermediateTOP2A-DNA covalent complex

Topoisomerase II poisons act by binding to the DNA topoisomerase 2-alpha-DNA cleavage complex and inhibiting the religation of the DNA strands, thereby stabilizing the covalent intermediate and inducing lethal DNA double-strand breaks (Nature Reviews Cancer, 2013; Nucleic Acids Research, 2009).