DNA Topoisomerase I and DNA Topoisomerase II (TOP1/TOP2)

DNA topoisomerases are essential nuclear enzymes that regulate the topological state of DNA by generating transient single-strand (Type I) or double-strand (Type II) breaks. These enzymes are critical for relieving torsional strain during DNA replication and transcription, as well as for ensuring proper chromosome segregation during mitosis [UniProt P11387, P11388]. In oncology, DNA Topoisomerase I and II are major therapeutic targets because rapidly dividing cancer cells exhibit a high dependency on these enzymes to maintain genomic stability and sustain proliferation [Nature Reviews Cancer, 2009]. Therapeutic agents targeting these enzymes, such as camptothecins (targeting TOP1) and anthracyclines or epipodophyllotoxins (targeting TOP2), primarily act as topoisomerase poisons. They stabilize the covalent DNA-enzyme cleavage complex, preventing DNA religation and causing lethal DNA breaks when replication forks or transcription machinery collide with the stabilized complexes [StatPearls, 2023]. While these inhibitors are cornerstone treatments for various solid tumors and hematologic malignancies, their clinical use is often limited by significant toxicities, including bone marrow suppression and potential cardiotoxicity [PubMed, 25403441]. Modern research continues to explore dual inhibitors and the use of predictive biomarkers like SLFN11 to enhance efficacy and mitigate resistance [Journal of Clinical Oncology, 2017].

Other names

TOP1TOP2TOP2ATOP2BDNA Topoisomerase 1DNA Topoisomerase 2Topoisomerase ITopoisomerase II

Stabilization of the DNA-enzyme covalent cleavage complex (topoisomerase poisoning) and inhibition of catalytic activity, leading to the accumulation of DNA strand breaks and subsequent apoptosis [StatPearls, 2023].