DNA topoisomerase 1 (Top1) - DNA covalent cleavage complex (Top1cc)

DNA topoisomerase 1 (Top1) is a vital enzyme that manages DNA topology by inducing transient single-strand breaks, forming a catalytic intermediate known as the Top1-DNA covalent cleavage complex (Top1cc) (Pommier, 2006, Nature Reviews Cancer). This complex is the specific molecular target for camptothecin derivatives like irinotecan and topotecan, which act as interfacial inhibitors by trapping the enzyme on the DNA (Thomas and Pommier, 2019, DNA Repair). By stabilizing the Top1cc, these drugs prevent DNA religation, leading to lethal double-strand breaks when the complex is encountered by replication forks or transcription machinery (Pommier et al., 2016, Chemical Reviews). This mechanism is widely utilized in the treatment of various solid tumors, including colorectal, ovarian, and small-cell lung cancers (National Cancer Institute). Resistance to Top1-targeted therapies is often linked to the activity of repair enzymes such as Tyrosyl-DNA phosphodiesterase 1 (TDP1) or the expression levels of Schlafen 11 (SLFN11) (Zoppoli et al., 2012, PNAS).

Other names

Top1ccTop1-DNA complexDNA topoisomerase 1 cleavage complexTop1-DNA covalent complexTop1-DNA covalent cleavage complex

Interfacial inhibition: The drug molecule binds at the interface of the Top1-DNA complex, stacking between the DNA base pairs at the cleavage site and the catalytic tyrosine residue of the enzyme, which prevents the religation of the DNA strand and traps the covalent complex (Pommier, 2006, Nature Reviews Cancer).