DNA topoisomerase 1-DNA cleavage complex (Top1-DNA CC) (Top1-DNA CC)

The DNA topoisomerase 1-DNA cleavage complex (Top1-DNA CC) is a transient, covalent intermediate formed during the catalytic cycle of the DNA topoisomerase 1 enzyme [1]. This enzyme is essential for maintaining genomic stability by relieving the torsional strain that accumulates during DNA replication, transcription, and chromatin remodeling [2]. In its normal function, the enzyme creates a single-strand break, attaches to the 3' end of the DNA, allows rotation, and then religates the strand [3]. However, certain therapeutic agents known as Top1 inhibitors, such as camptothecin derivatives, act as interfacial inhibitors by binding at the site of the DNA cleavage and trapping the enzyme in this covalent state [4]. These stabilized complexes act as physical barriers; when they collide with advancing replication forks, they are converted into lethal double-strand breaks, triggering apoptosis in rapidly dividing cancer cells [5]. Consequently, the Top1-DNA CC is a validated target for several FDA-approved chemotherapies used to treat colorectal, ovarian, and lung cancers [6]. The efficacy of targeting this complex is often modulated by cellular repair mechanisms, such as those involving tyrosyl-DNA phosphodiesterase 1 (TDP1), which can resolve the trapped complexes [7].

Other names

Top1ccTopoisomerase I-DNA covalent complexTop1-DNA complexTrapped Topoisomerase I

Stabilization of the covalent Top1-DNA intermediate (interfacial inhibition), preventing DNA religation and causing replication-mediated double-strand breaks [3, 4].