DNA topoisomerase 1–DNA cleavage complex (TOP1cc) (TOP1cc)

The DNA topoisomerase 1–DNA cleavage complex (TOP1cc) is a transient intermediate formed during the catalytic cycle of DNA topoisomerase 1 (TOP1), an essential enzyme that relieves torsional strain in DNA during replication and transcription (Pommier, 2006, Nature Reviews Cancer). TOP1 functions by creating a single-strand break, forming a covalent phosphotyrosyl bond with the 3' end of the DNA, allowing the strand to rotate before religation (UniProt P11387). In the presence of TOP1 inhibitors like camptothecins, these complexes are stabilized and persist on the DNA, a process known as 'trapping' (Thomas et al., 2004, Chemical Reviews). When DNA or RNA polymerases collide with these trapped TOP1cc, they generate irreversible double-strand breaks, which ultimately lead to cell cycle arrest and programmed cell death (Pommier, 2013, Nature Reviews Drug Discovery). Because rapidly dividing cancer cells rely heavily on TOP1 for genomic stability, TOP1cc is a major therapeutic target in oncology, particularly for colorectal and lung cancers. However, the effectiveness of targeting TOP1cc can be limited by DNA repair enzymes like TDP1, which can resolve these complexes, and safety concerns often involve systemic toxicities such as myelosuppression and severe diarrhea (StatPearls, 2023).

Other names

Topoisomerase I–DNA covalent complexTOP1-DNA covalent complexTOP1 cleavage complexTopoisomerase 1-DNA complex

Stabilization and trapping of the transient TOP1-DNA covalent intermediate, preventing DNA religation and causing lethal double-strand breaks upon collision with replication forks (Pommier, 2006, Nature Reviews Cancer).