DNA-Topoisomerase I cleavage complex (Top1cc) (Top1cc)

The DNA-Topoisomerase I cleavage complex (Top1cc) is a transient intermediate formed during the catalytic cycle of Topoisomerase I (Top1), an enzyme essential for relieving DNA torsional strain during replication, transcription, and repair [PMID: 29433136]. Under normal conditions, Top1 creates a single-strand break, forms a covalent bond with the 3-phosphate end of the DNA, allows the DNA to rotate to relieve supercoiling, and then religates the strand [PMID: 16437129]. However, certain chemotherapeutic agents, most notably camptothecin derivatives like irinotecan and topotecan, act as interfacial inhibitors that bind to the Top1cc, trapping the enzyme on the DNA and preventing religation [PMID: 22749833]. These stabilized complexes become lethal lesions when they collide with advancing replication forks or transcription machinery, resulting in permanent double-strand breaks and triggering apoptosis [PMID: 19758515]. Because rapidly dividing cancer cells have higher rates of DNA replication, they are particularly susceptible to the accumulation of Top1cc-induced damage, making this complex a critical target in oncology [PMID: 24711446]. Beyond camptothecins, novel inhibitors like indenoisoquinolines are being developed to target this complex with improved stability and reduced susceptibility to resistance mechanisms [PMID: 29433136]. The repair of these complexes is primarily managed by the enzyme Tyrosyl-DNA phosphodiesterase 1 (TDP1), and its activity levels can influence the efficacy of Top1-targeted therapies [PMID: 30305475].

Other names

Top1-DNA covalent complexTopoisomerase I-DNA complexTop1 cleavage complex

Stabilization of the transient covalent complex between DNA and Topoisomerase I (interfacial inhibition), which prevents DNA religation and leads to lethal double-strand breaks upon collision with replication forks [PMID: 22749833].