Topoisomerase II-DNA cleavage complex (TOP2cc) (TOP2cc)

The Topoisomerase II-DNA cleavage complex (TOP2cc) is a transient, covalent intermediate formed during the catalytic cycle of type II topoisomerases, where the enzyme subunits are linked to the 5' ends of a double-strand DNA break [1, 10]. This complex is physiologically essential for managing DNA topology, including the resolution of supercoils, knots, and catenanes that occur during DNA replication, transcription, and chromosome segregation [3, 7, 13]. Therapeutic agents known as topoisomerase II poisons, such as etoposide and doxorubicin, target this complex by stabilizing it and preventing the religation of the DNA strands [1, 6, 16]. This stabilization effectively converts the enzyme into a cellular toxin, resulting in the accumulation of permanent double-strand breaks that trigger apoptosis in rapidly dividing cells [1, 10, 12]. While these drugs are widely used in cancer chemotherapy, the stabilization of TOP2cc is also linked to severe adverse effects, including cardiotoxicity and the induction of secondary leukemias through chromosomal translocations [9, 16, 18]. The dual nature of the complex as both an essential biological intermediate and a potent source of genomic instability makes it a highly effective but high-risk target in oncology [1, 12].

Other names

DNA and Topoisomerase II–DNA cleavage complexTopoisomerase II-DNA covalent complexTopoisomerase II-DNA adductTopoisomerase II-DNA protein crosslinkTOP2-DPCCleavable complex

Topoisomerase II poisons stabilize the covalent cleavage complex by inhibiting the religation of double-strand DNA breaks, leading to genomic fragmentation and apoptosis.