DNA topoisomerase 2-alpha and 2-beta (TOP2A/TOP2B)

DNA topoisomerase 2-alpha and 2-beta (TOP2A and TOP2B) are essential enzymes that regulate the topological state of DNA by creating transient double-strand breaks to resolve entanglements such as supercoiling, knotting, and catenation [1, 9]. TOP2A is primarily expressed in proliferating cells and is indispensable for DNA replication and chromosome segregation during mitosis, while TOP2B is constitutively expressed and plays a key role in transcription and neural development [1, 11, 15]. These enzymes are major therapeutic targets in oncology, particularly for topoisomerase II poisons like etoposide and doxorubicin, which stabilize the enzyme-DNA covalent intermediate to induce lethal DNA damage in cancer cells [5, 12, 18]. Despite their high efficacy in treating various solid and hematological malignancies, drugs targeting this complex are associated with significant safety concerns, including dose-limiting cardiotoxicity and the risk of secondary leukemias [1, 5, 18]. Current research efforts are directed toward developing isoform-selective inhibitors to enhance therapeutic efficacy while minimizing long-term toxicities [11, 18].

Other names

Topoisomerase IITopo IIDNA topoisomerase IIDNA topoisomerase (ATP-hydrolyzing)DNA topoisomerase 2-alphaDNA topoisomerase 2-beta

Topoisomerase II poisons stabilize the covalent DNA-TOP2 cleavage complex, preventing DNA religation and inducing double-strand breaks that trigger apoptosis; topoisomerase II catalytic inhibitors block enzymatic activity such as ATPase activity or DNA binding without trapping the cleavage complex.