DNA within DNA topoisomerase 1-DNA complexes (TOP1cc) (TOP1cc)

DNA within DNA topoisomerase 1 (TOP1) complexes refers to the DNA substrate as it exists in a transient covalent intermediate with the TOP1 enzyme during the relaxation of DNA supercoiling. This intermediate, known as the TOP1-DNA cleavage complex (TOP1cc), is formed when TOP1 cleaves one strand of the DNA phosphodiester backbone to allow rotation and relief of torsional strain (Pommier, 2006, Nature Reviews Cancer). Under normal physiological conditions, these complexes are short-lived as the enzyme quickly religates the DNA. However, certain chemotherapeutic agents, such as camptothecins and their derivatives (e.g., irinotecan, topotecan), act as interfacial inhibitors that bind specifically to the TOP1cc, trapping the enzyme on the DNA (Pommier et al., 2013, Chemical Reviews). These stabilized complexes pose a significant threat to genomic integrity; when DNA or RNA polymerases collide with the trapped TOP1cc, the single-strand breaks are converted into permanent, lethal double-strand breaks (DSBs) (Koster et al., 2007, Nature). This mechanism triggers DNA damage response pathways and ultimately leads to programmed cell death, making the TOP1-DNA complex a critical target in the treatment of various cancers, including colorectal, lung, and ovarian malignancies.

Other names

TOP1-DNA cleavage complexTOP1ccDNA topoisomerase 1-DNA covalent complexCleavable complexTOP1-DNA covalent complex

Interfacial inhibition where the drug binds at the junction of the TOP1 enzyme and the cleaved DNA strand, preventing DNA religation and leading to replication-mediated double-strand breaks.