DNA topoisomerase I-DNA and DNA topoisomerase II-DNA cleavable complexes (TOP1-DNA and TOP2-DNA CCs)

DNA topoisomerase I-DNA and DNA topoisomerase II-DNA cleavable complexes are transient intermediates formed during the catalytic cycle of topoisomerase enzymes, which are essential for managing DNA supercoiling and entanglement during replication, transcription, and chromosome segregation [1]. Topoisomerase I (TOP1) creates single-strand breaks, while Topoisomerase II (TOP2) creates double-strand breaks to allow DNA strands to pass through one another [2]. In a healthy cell, these breaks are rapidly re-ligated to maintain genomic integrity. However, certain chemotherapeutic agents, known as topoisomerase poisons, bind to these complexes and stabilize them, preventing the re-sealing of the DNA [1, 3]. This stabilization leads to the accumulation of permanent DNA strand breaks when the replication fork or transcription machinery collides with the trapped complex [2]. The resulting genomic instability triggers programmed cell death (apoptosis), making these complexes a critical target in oncology [3]. Drugs targeting these complexes, such as camptothecins for TOP1 and anthracyclines or epipodophyllotoxins for TOP2, are widely used to treat various solid tumors and hematological malignancies [4].

Other names

Topoisomerase-DNA covalent complexesTopoisomerase-DNA cleavage complexesTopo-DNA complexesTOP1CCTOP2CCTopoisomerase-DNA adducts

Stabilization of the transient covalent intermediate (cleavable complex) between the topoisomerase enzyme and DNA, preventing the re-ligation of DNA strands and leading to lethal DNA strand breaks during replication or transcription [1, 2].