DNA topoisomerase 1–DNA covalent cleavage complex (Top1cc)

The DNA topoisomerase 1–DNA covalent cleavage complex (Top1cc) is a transient intermediate formed during the catalytic cycle of the Top1 enzyme, which is essential for relieving DNA torsional strain during replication and transcription (Pommier, 2006, Nature Reviews Cancer). Top1 functions by creating a single-strand break in the DNA and forming a covalent bond between its active site tyrosine and the 3' phosphate of the DNA backbone (Champoux, 2001, Annual Review of Biochemistry). Under normal conditions, this complex is short-lived as the enzyme religates the DNA after rotation. However, certain chemotherapeutic agents, most notably camptothecin derivatives like irinotecan and topotecan, act as interfacial inhibitors that bind specifically to this complex and prevent religation (Pommier et al., 2014, Chemical Reviews). This trapping of Top1cc leads to lethal double-strand DNA breaks when the complex collides with advancing replication forks or transcription machinery, ultimately triggering apoptosis in rapidly dividing cancer cells (Murai et al., 2012, Cancer Cell). The repair of these complexes is primarily mediated by the enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1), which hydrolyzes the bond between Top1 and DNA. Consequently, Top1cc is a validated clinical target for various solid tumors, including colorectal and lung cancers (National Cancer Institute, 2023).

Other names

Top1-DNA cleavage complexTop1ccTopoisomerase I-DNA complexTop1-DNA covalent complexTop1-DNA CC

Interfacial inhibition; the drug binds at the interface of the Top1 enzyme and the cleaved DNA, sterically hindering the religation of the DNA strand and trapping the covalent complex (Pommier, 2013, ACS Chemical Biology).