DNA topoisomerase I–DNA cleavage complex (Top1cc)

The **DNA topoisomerase I–DNA cleavage complex** (Top1cc) is a transient covalent intermediate formed during the catalytic cycle of DNA topoisomerase I, an enzyme essential for regulation of DNA topology during vital cellular processes such as replication, transcription, and recombination[3][1][2][6]. In this complex, the active site tyrosine of topoisomerase I forms a covalent bond with the 3′-phosphate (type IB, e.g., human TOP1) or 5′-phosphate (type IA, e.g., bacterial TopoI) of DNA at a single-strand break. This allows controlled rotation or passage of DNA strands to relieve topological stress such as supercoiling, after which the enzyme normally religates the break, restoring DNA integrity[3][6][1]. Topoisomerase I–DNA cleavage complexes are *therapeutically exploited* by drugs such as camptothecin and its derivatives, which trap the enzyme on DNA by preventing religation, leading to persistent DNA breaks and cell death—making this complex a critical **antibacterial and anticancer drug target**[1][3][2]. Excess or trapped cleavage complexes are cytotoxic and are associated with genomic instability and cancer, as well as with some off-target toxicities in normal tissues[3][1]. Trapping of this complex forms the principal mechanism of action for topoisomerase I–targeting agents used clinically and in drug discovery[1][3].

Other names

Topoisomerase I cleavage complexTop1–DNA cleavage complexTop1ccCovalent Topoisomerase I–DNA complex

Drugs (e.g., camptothecin and derivatives) stabilize the covalent Topoisomerase I–DNA cleavage complex, preventing religation of DNA, which leads to DNA strand breaks, replication fork collision, DNA damage, and cell death[3][1][2].