DNA within the DNA Topoisomerase II–DNA cleavage complex (TOP2cc) (TOP2cc)

DNA within the DNA Topoisomerase II–DNA cleavage complex (TOP2cc) is a transient but essential intermediate formed during the catalytic cycle of Topoisomerase II (TOP2) enzymes, which regulate DNA supercoiling, decatenation, and knotting (Pommier et al., 2016, Nature Reviews Cancer). In this complex, the TOP2 enzyme creates a double-strand break and becomes covalently linked to the 5' phosphate ends of the DNA via a tyrosyl-DNA phosphodiester bond (Deweese & Osheroff, 2009, Nucleic Acids Research). This specific DNA-protein interface is the pharmacological target for "TOP2 poisons," such as etoposide and doxorubicin, which act by stabilizing the cleavage complex and preventing the religation of the DNA strands (Nitiss, 2009, Nature Reviews Cancer). The stabilization of TOP2cc converts a necessary cellular process into a source of persistent double-strand breaks, which are recognized by the cell's DNA damage response machinery, leading to cell cycle arrest and apoptosis (StatPearls, 2023). While highly effective in treating various cancers, including leukemias and solid tumors, targeting this complex carries risks such as cardiotoxicity—often linked to TOP2B in cardiomyocytes—and the potential for secondary malignancies due to chromosomal translocations (Zhang et al., 2012, Nature Medicine).

Other names

TOP2-DNA cleavage complexTopoisomerase II-DNA covalent complexTOP2cc-DNADNA-TOP2 covalent complex

Stabilization of the transient covalent DNA Topoisomerase II–DNA cleavage complex, which inhibits DNA religation and leads to the accumulation of double-strand breaks (Pommier et al., 2016, Nature Reviews Cancer).