DNA topoisomerase 1–DNA cleavable complex (Top1cc) (Top1cc)

The DNA topoisomerase 1–DNA cleavable complex (Top1cc) is a transient catalytic intermediate formed when the enzyme DNA topoisomerase 1 (Top1) nicks a single strand of DNA to relieve torsional strain during replication and transcription (Pommier, Nat Rev Cancer, 2006; Champoux, Annu Rev Biochem, 2001). In this state, the enzyme is covalently linked to the 3' phosphate end of the DNA via a tyrosyl-DNA phosphodiester bond (Pommier et al., Chem Rev, 2016). This complex is the primary molecular target for camptothecin-derived chemotherapeutic agents, which act as interfacial inhibitors by binding at the site of the DNA cleavage (Pommier, Nat Rev Cancer, 2006). By stabilizing the Top1cc, these drugs prevent the religation of the DNA strand, effectively trapping the enzyme on the DNA (Pommier et al., Chem Rev, 2016). When advancing replication forks or transcription complexes collide with these trapped Top1ccs, they are converted into lethal double-strand breaks, triggering apoptosis (Thomas et al., Clin Cancer Res, 2017). This mechanism makes Top1cc a critical target in the treatment of various malignancies, including colorectal and small cell lung cancers (Pommier, Nat Rev Cancer, 2006).

Other names

DNA topoisomerase I–DNA cleavable complexTop1-DNA covalent complexTopoisomerase I cleavage complexTop1-DNA complexTop1-DNA covalent intermediate

Stabilization of the transient covalent Top1-DNA complex, inhibiting DNA religation and causing replication-mediated DNA damage.