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 catalytic intermediate formed during the action of the enzyme DNA topoisomerase 1. Under normal physiological conditions, Top1 relieves torsional strain in DNA by creating a reversible single-strand break, forming a covalent bond between a tyrosine residue and the 3' phosphate of the DNA backbone [1, 2]. This allows the DNA to rotate and relax before the enzyme re-ligates the strand. However, this complex becomes a potent therapeutic target when stabilized by specific inhibitors, such as camptothecin derivatives [1, 3]. These drugs act as interfacial inhibitors, trapping the Top1-DNA CC and preventing the re-ligation step [2]. When DNA replication forks or transcription machinery encounter these stabilized complexes, they are converted into permanent, lethal double-strand breaks, ultimately triggering programmed cell death [1, 3]. This mechanism is widely exploited in oncology for the treatment of various solid tumors, including colorectal and ovarian cancers [1, 4]. Citations: [1] Pommier Y. (2006). Nature Reviews Cancer. [2] Pommier Y. (2013). ACS Chemical Biology. [3] Thomas C. J., et al. (2004). Bioorganic & Medicinal Chemistry. [4] UniProt (2024). P11387 (TOP1_HUMAN).

Other names

Top1ccTopoisomerase I-DNA covalent complexTop1-DNA covalent complexTop1-DNA adductTop1 cleavage complex

Interfacial inhibition; stabilization of the covalent Top1-DNA intermediate to prevent re-ligation, resulting in replication-mediated DNA double-strand breaks.