DNA-topoisomerase I complex (Top1cc)

The DNA-topoisomerase I complex is a transient, covalent intermediate formed during the catalytic cycle of the topoisomerase I (TOP1) enzyme. TOP1 is a critical nuclear enzyme that relieves torsional strain in DNA by creating reversible single-strand breaks, allowing the DNA to rotate and relax during replication and transcription (Pommier, 2006, Nature Reviews Cancer; UniProt P11387). During this process, the enzyme becomes covalently linked to the 3'-phosphate end of the DNA, forming what is known as the Top1-DNA cleavage complex (Top1cc) (Thomas et al., 2004, Chemical Reviews). This complex is the specific molecular target for camptothecin-based drugs and their derivatives, which act as topoisomerase poisons by binding at the enzyme-DNA interface (Pommier, 2013, Nature Reviews Cancer). By stabilizing the Top1cc, these drugs prevent the religation of the DNA strand, effectively trapping the enzyme on the DNA. When advancing replication forks or transcription complexes collide with these trapped Top1cc units, they generate lethal double-strand breaks that trigger apoptosis (Murai et al., 2012, Cell Reports). Clinically, targeting this complex is a cornerstone in the treatment of various malignancies, including colorectal, lung, and ovarian cancers.

Other names

DNA and DNA–topoisomerase I complexTopoisomerase I-DNA cleavage complexTop1-DNA complexDNA-topoisomerase I covalent complexTOP1-DNA cleavage complex

Stabilization of the covalent DNA-topoisomerase I cleavage complex (interfacial inhibition), preventing DNA religation and causing replication-mediated double-strand breaks.