DNA topoisomerase 1 – DNA covalent complex (TOP1cc)

DNA topoisomerase 1 (TOP1) is an essential enzyme that manages DNA topology by relieving torsional strain during replication, transcription, and repair [1, 2]. It achieves this by creating a transient single-strand break, forming a covalent bond between its catalytic tyrosine and the 3'-phosphate of the DNA backbone, a state known as the TOP1-DNA covalent complex (TOP1cc) [5, 8]. This complex is the specific therapeutic target for 'TOP1 poisons' such as camptothecin and its clinical derivatives, irinotecan and topotecan [1, 13]. These drugs function as interfacial inhibitors, trapping the enzyme in the covalent complex and preventing the religation of the DNA strand [3, 7]. The resulting persistent DNA-protein adducts act as physical barriers that collide with advancing replication and transcription machinery, converting single-strand nicks into permanent, lethal double-strand breaks [1, 14]. This mechanism selectively kills rapidly proliferating cancer cells, making the TOP1-DNA covalent complex a cornerstone target in the treatment of various solid tumors, including colorectal, ovarian, and lung cancers [2, 11].

Other names

TOP1 cleavage complexTOP1ccDNA topoisomerase 1-DNA adductTOP1-DNA intermediateTOP1-DNA phosphotyrosyl complex

Interfacial inhibition; stabilization of the transient TOP1-DNA covalent complex (cleavage complex) by binding at the cleavage site, which prevents DNA religation and leads to lethal double-strand breaks upon collision with replication or transcription forks [1, 3, 13].