DNA topoisomerase II alpha (TOP2A) and DNA topoisomerase II beta (TOP2B) (TOP2A / TOP2B)

DNA topoisomerase II alpha (TOP2A) and DNA topoisomerase II beta (TOP2B) are essential eukaryotic enzymes that manage DNA topology by producing transient double-strand breaks to resolve tangles and supercoils that arise during DNA replication and transcription. They act as homodimers using ATP hydrolysis to pass one double-stranded DNA segment through another and then religate the break. TOP2A is critical for cell proliferation and chromosome segregation during mitosis, whereas TOP2B has more specialized roles in transcriptional regulation and development. Both forms are frontline targets for various anticancer agents, whose cytotoxicity predominantly derives from induction of irreversible DNA breaks. Mutations or aberrant regulation can confer drug resistance or underlie human diseases, including certain neurodevelopmental syndromes and cancers.

Other names

Topoisomerase II alphaTopoisomerase II betaTop2αTop2βType II topoisomerase alpha (for TOP2A)Type II topoisomerase beta (for TOP2B)DNA Topo IIα (for TOP2A)DNA Topo IIβ (for TOP2B)

Drugs targeting TOP2A/B act primarily by stabilizing the “cleavage complex,” which prevents the religation of DNA and causes irreversible DNA double-strand breaks. Another mechanism involves catalytic inhibition, preventing the ATPase activity or DNA religation step. Both mechanisms ultimately lead to the induction of DNA damage response and apoptosis, especially in rapidly proliferating cells.