DNA at Topoisomerase II cleavage sites (DNA-TOP2 cleavage sites)

DNA at Topoisomerase II (TOP2) cleavage sites refers to the specific genomic regions where the TOP2 enzyme introduces transient double-strand breaks to resolve topological constraints during DNA metabolism (Nitiss, 2009, Nature Reviews Cancer). Under physiological conditions, TOP2 facilitates the passage of one DNA duplex through another by forming a covalent intermediate known as the cleavage complex (TOP2cc), which is rapidly resolved through religation (Pommier et al., 2016, Nature Reviews Drug Discovery). This site becomes a primary therapeutic target for a class of drugs called TOP2 poisons, which bind to the enzyme-DNA interface and stabilize the TOP2cc, preventing the enzyme from sealing the DNA breaks (Deweese & Osheroff, 2009, Nucleic Acids Research). The accumulation of these stabilized complexes leads to persistent double-strand breaks, which are recognized by the cell's damage response machinery, ultimately triggering programmed cell death (Vann et al., 2021, Journal of Biological Chemistry). While highly effective in treating various cancers, targeting these sites carries risks such as secondary leukemias due to chromosomal translocations occurring at the cleavage sites (Cowell & Austin, 2012, Int. J. Environ. Res. Public Health). Additionally, TOP2B-mediated cleavage at specific sites in non-dividing cells, such as cardiomyocytes, is implicated in the cardiotoxicity associated with certain anthracyclines (Zhang et al., 2012, Nature Medicine).

Other names

Topoisomerase II-DNA covalent complexesTOP2ccTopoisomerase II-DNA cleavage complexesDNA-TOP2 complexesTOP2-DNA interface

Stabilization of the covalent Topoisomerase II-DNA cleavage complex (TOP2cc) to prevent DNA religation, leading to the accumulation of permanent double-strand breaks and subsequent induction of apoptosis.