DNA topoisomerase 1–DNA cleavable complex (TOP1-DNA CC)

DNA topoisomerase 1 (TOP1) is a vital enzyme responsible for managing DNA topology by relieving torsional strain during replication, transcription, and repair (Pommier, 2006, Nature Reviews Cancer) [1]. The enzyme functions by creating a transient single-strand break in the phosphodiester backbone, forming a covalent intermediate known as the TOP1–DNA cleavable complex (TOP1cc) (Pommier et al., 2016, Chemical Reviews) [2]. While this complex is normally short-lived, it becomes a primary therapeutic target for a class of anticancer drugs known as TOP1 poisons (Pommier, 2006, Nature Reviews Cancer) [1]. These drugs, including camptothecin derivatives like irinotecan and topotecan, act as interfacial inhibitors that bind at the junction of the enzyme and DNA (Thomas et al., 2004, Bioorganic & Medicinal Chemistry) [3]. By stabilizing the TOP1cc, these agents prevent the religation of the DNA strand, effectively trapping the enzyme on the DNA (Pommier et al., 2016, Chemical Reviews) [2]. When advancing replication forks or transcription complexes collide with these stabilized complexes, they are converted into irreversible double-strand breaks (Pommier, 2006, Nature Reviews Cancer) [1]. This accumulation of DNA damage triggers cell cycle arrest and eventually leads to programmed cell death or apoptosis (Pommier et al., 2016, Chemical Reviews) [2]. Consequently, the TOP1–DNA cleavable complex serves as a critical molecular trap used to selectively eliminate rapidly proliferating malignant cells (Murai et al., 2012, Cancer Research) [4].

Other names

Top1ccTopoisomerase I-DNA covalent complexTop1-DNA cleavage complexTOP1-DNA covalent intermediate

Interfacial inhibition that stabilizes the transient covalent DNA-enzyme intermediate, preventing DNA religation and causing lethal double-strand breaks upon collision with replication or transcription machinery.