DNA topoisomerase 1–DNA cleavage complex (TOP1cc)

The DNA topoisomerase 1–DNA cleavage complex (TOP1cc) is a transient, covalent intermediate formed during the catalytic cycle of DNA topoisomerase 1 (TOP1), an essential enzyme that relieves torsional strain in DNA (Pommier, 2013). During this process, TOP1 creates a single-strand break and attaches covalently to the 3'-phosphate end of the DNA via its active-site tyrosine residue, Tyr723 (NIH, 2021). This complex is the specific molecular target for a class of anticancer agents known as topoisomerase I poisons, including camptothecin and its derivatives like irinotecan and topotecan (Deweese and Osheroff, 2009). These drugs act as interfacial inhibitors by binding at the enzyme-DNA interface and preventing the religation of the DNA strand, thereby trapping the enzyme on the DNA (Pommier, 2013). The stabilized TOP1cc becomes a lethal lesion when it collides with advancing replication or transcription forks, leading to irreversible double-strand breaks and triggering apoptosis (NIH, 2021). Consequently, TOP1cc is a critical target in the treatment of various solid tumors, including colorectal and small cell lung cancer, although its efficacy can be influenced by DNA repair mechanisms such as those involving tyrosyl-DNA phosphodiesterase 1 (TDP1) (Pommier, 2013).

Other names

Topoisomerase I-DNA complexTOP1-DNA covalent complexCleavable complexTopoisomerase I-DNA-enzyme complexTOP1cc

Interfacial inhibition of DNA religation, where the drug traps the covalent DNA topoisomerase 1–DNA cleavage complex (TOP1cc), preventing the restoration of the DNA phosphodiester backbone and leading to lethal double-strand breaks upon collision with replication or transcription machinery (Pommier, 2013; Deweese and Osheroff, 2009).