DNA-topoisomerase I cleavage complex (Top1cc)

The DNA-topoisomerase I cleavage complex (Top1cc) is a transient, covalent intermediate formed during the catalytic cycle of the enzyme topoisomerase I (Top1). Top1 is essential for relieving torsional strain in DNA by creating a single-strand nick, allowing the DNA to rotate and relax supercoils generated during replication and transcription [4, 11]. Under normal conditions, Top1 quickly religates the DNA and dissociates; however, certain conditions or drugs can trap the enzyme in this covalent state [4, 13]. In oncology, Top1cc is the primary target of "Top1 poisons" such as camptothecin and its derivatives, irinotecan and topotecan [1, 8]. These drugs act as interfacial inhibitors, binding at the junction of the enzyme and DNA to prevent religation [8, 9]. The resulting persistent Top1cc lesions lead to lethal double-strand breaks upon collision with replication or transcription forks, making them highly effective at inducing apoptosis in rapidly proliferating cancer cells [1, 13]. Beyond cancer, the inability to repair endogenous Top1cc is linked to neurodegenerative disorders like spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) [4, 16].

Other names

Top1-DNA cleavage complexTopoisomerase I-DNA covalent complexTop1-DNA intermediateCleavable complexTop1cc

Interfacial inhibition by stabilizing the covalent DNA-enzyme complex and preventing DNA religation, leading to replication fork collision and double-strand breaks.