DNA topoisomerase 1-DNA cleavage complex (TOP1cc) (TOP1cc)

The DNA topoisomerase 1-DNA cleavage complex (TOP1cc) is a transient catalytic intermediate formed when the enzyme DNA topoisomerase 1 (TOP1) cleaves a single strand of the DNA double helix to relieve torsional strain (Pommier, 2006, Nature Reviews Cancer). Under physiological conditions, TOP1 creates a covalent 3'-phosphotyrosyl bond with the DNA, allows for controlled strand rotation, and rapidly religates the nick to restore DNA integrity (Champoux, 2001, Annual Review of Biochemistry). This complex becomes a potent therapeutic target when stabilized by interfacial inhibitors such as camptothecin and its derivatives, irinotecan and topotecan (Pommier et al., 2016, Chemical Reviews). These drugs bind at the site of the DNA cleavage, preventing the religation step and trapping the enzyme on the DNA. When advancing replication forks or transcription complexes collide with these stabilized TOP1ccs, they are converted into lethal double-strand breaks (Koster et al., 2007, Nature). These persistent lesions trigger DNA damage responses and ultimately lead to programmed cell death in rapidly dividing cells. Consequently, TOP1cc is a validated target for the treatment of various solid tumors, including colorectal, ovarian, and lung cancers. The clinical efficacy of targeting TOP1cc is often influenced by the expression of DNA repair enzymes like Tyrosyl-DNA phosphodiesterase 1 (TDP1) and the biomarker SLFN11 (Pommier, 2009, ACS Chemical Biology).

Other names

TOP1-DNA covalent complexTopoisomerase I-DNA cleavage complexTOP1-DNA CCCamptothecin-TOP1-DNA ternary complex

Interfacial inhibition of DNA religation by stabilizing the covalent TOP1-DNA intermediate, leading to replication-mediated double-strand breaks.