DNA-topoisomerase II-cisplatin complex (TOP2-DNA-Pt complex)

The DNA-topoisomerase II-cisplatin complex is a ternary structure formed when the enzyme Topoisomerase II (TOP2) interacts with DNA that has been modified by the chemotherapy drug cisplatin (Osheroff et al., 1994). Cisplatin creates bulky intrastrand crosslinks that distort the DNA double helix, which serves as the primary signal for cellular damage (Jamieson & Lippard, 1999). Under normal conditions, TOP2 manages DNA topology by creating transient double-strand breaks; however, the presence of cisplatin adducts prevents the enzyme from resealing these breaks (Bubley et al., 1996). This trapping of the enzyme in a covalent cleavable complex converts a necessary cellular process into a source of permanent, lethal DNA damage (Nitiss, 2009). The resulting accumulation of double-strand breaks is a potent trigger for the apoptotic cascade in malignant cells (Siddik, 2003). This specific interaction explains the clinical synergy observed when platinum agents are combined with TOP2 poisons like etoposide (Kaufmann, 1991). Consequently, this complex is a major determinant of the efficacy of combination chemotherapy regimens in treating various cancers (Pommier et al., 2010).

Other names

Cisplatin-DNA-Topoisomerase II ternary complexCisplatin-poisoned Topoisomerase IICisplatin-DNA-TOP2 cleavable complexPlatinum-DNA-topoisomerase II complex

Cisplatin-DNA adducts act as topoisomerase II poisons by stabilizing the covalent cleavable complex, preventing DNA religation and leading to irreversible double-strand breaks and apoptosis.