DNA topoisomerase 1 and 2 (TOP1/TOP2)

DNA topoisomerases I and II are essential nuclear enzymes that regulate the topological state of DNA by introducing transient breaks in the phosphodiester backbone to relieve torsional strain. Topoisomerase I (TOP1) functions by creating single-strand breaks to relax DNA supercoiling, while Topoisomerase II (TOP2) creates double-strand breaks to allow the passage of one DNA duplex through another, essential for chromosome segregation [UniProt: P11387, P11388]. These enzymes are critical for DNA replication, transcription, and repair, making them vital for the survival of rapidly proliferating cells. In oncology, they are major therapeutic targets because cancer cells often overexpress these enzymes to manage high genomic activity. Drugs targeting these enzymes, such as camptothecins for TOP1 and anthracyclines or epipodophyllotoxins for TOP2, trap the enzyme on DNA, resulting in catastrophic genomic instability and programmed cell death [NIH: National Cancer Institute]. While highly effective in treating various solid tumors and hematologic malignancies, these agents are associated with significant toxicities, including bone marrow suppression and potential long-term risks like secondary leukemias or cardiomyopathy.

Other names

DNA topoisomerase IDNA topoisomerase IITOP1TOP2ATOP2BType I topoisomeraseType II topoisomeraseDNA topoisomerase (ATP-hydrolyzing)

Topoisomerase inhibitors primarily act as 'topoisomerase poisons' by binding to and stabilizing the transient covalent enzyme-DNA complex (the cleavable complex). This prevents the re-ligation of the DNA strands, leading to the accumulation of single-strand breaks (TOP1) or double-strand breaks (TOP2). When replication forks or transcription machinery encounter these stabilized complexes, they convert them into permanent, lethal DNA damage, which triggers cell cycle arrest and apoptosis [PubMed: PMC3057097, StatPearls: Topoisomerase Inhibitors].