DNA topoisomerase I-DNA covalent complex (Top1-DNA complex)

The DNA topoisomerase I-DNA covalent complex is a transient intermediate formed during the catalytic cycle of DNA topoisomerase I, an enzyme that relaxes supercoiled DNA by nicking one strand, allowing controlled rotation, and then religating the break[2][3][5][9]. This intermediate involves a covalent bond between a tyrosine residue in the enzyme and the 3’ phosphate end of the cleaved DNA strand[3][5]. Normally, this complex is short-lived, but it can be stabilized by certain drugs, leading to persistent DNA breaks and cell death—a mechanism exploited by camptothecin and its derivatives for anticancer therapy[2][4][6][8]. As a drug target, stabilization of the Top1-DNA complex leads to replication- and transcription-associated DNA damage, making it particularly cytotoxic to proliferating cells[2][6]. The efficacy of these drugs can be modulated by cellular DNA repair capacity and TOP1 expression, making the complex both a therapeutic target and a potential biomarker for cancer treatment response[6][10]. Safety concerns revolve primarily around damage to non-cancerous proliferative tissues, resulting in characteristic chemotherapy toxicities[6].

Other names

Topoisomerase I-DNA complexTop1-DNA complexTopoisomerase I covalent complexTopoisomerase I cleavage complexTop1cc

Stabilization of the covalent Top1-DNA complex (Top1 poisons); Inhibition of religation step, leading to persistent single-strand or double-strand DNA breaks