DNA topoisomerase I and DNA topoisomerase II alpha (TOP1 and TOP2A)

DNA topoisomerase I and DNA topoisomerase II alpha are essential nuclear enzymes that regulate the topology of DNA during replication, transcription, recombination, and chromosome segregation. DNA topoisomerase I (TOP1) cleaves a single strand of DNA to relieve torsional strain during replication and transcription, then reseals the break; it does not require ATP. DNA topoisomerase II alpha (TOP2A) is a homodimeric enzyme that introduces transient double-stranded DNA breaks using ATP hydrolysis and is vital for chromosomal decatenation, especially during mitosis. Both enzymes are validated antineoplastic targets: small-molecule inhibitors exert cytotoxicity largely by stabilizing transient cleavable complexes between the enzyme and DNA, converting physiological DNA-processing intermediates into permanent DNA breaks that trigger cell death. Overexpression or gene amplification of TOP2A is observed in some rapidly proliferating tumors, supporting its role in cancer biology. Despite their therapeutic utility, topoisomerase inhibitors are associated with risks including myelosuppression, secondary leukemia (following type II inhibitor exposure), and off-target toxicities such as cardiotoxicity and mucositis.

Other names

TOP1Topo IDNA topoisomerase type ITOP2ATopo II alphaDNA topoisomerase type II alpha

Stabilization of the covalent topoisomerase-DNA cleavage complex (“poisoning”), leading to DNA breaks and cytotoxicity. Inhibition of DNA religation or induction of enzyme-mediated DNA fragmentation.