DNA topoisomerase 2-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, which are essential enzymes that manage DNA topology by resolving knots and tangles [1, 6]. During its function, the enzyme creates a double-stranded break in a "gate" DNA segment, covalently binds to the 5' ends, and passes another DNA duplex through the gap before religating the break [3, 5, 7]. This complex is the specific target of "topoisomerase II poisons," such as etoposide and anthracyclines, which stabilize the intermediate and prevent the religation of the DNA strands [4, 8, 13]. By trapping the enzyme in this state, these drugs convert an essential cellular machine into a potent toxin that generates persistent double-strand breaks, ultimately triggering apoptosis in rapidly proliferating cancer cells [1, 10, 15]. However, the persistence of TOP2cc can also lead to deleterious genomic rearrangements, such as MLL gene translocations, which are associated with the development of secondary leukemias [3, 9, 14]. Furthermore, the interaction of drugs with the TOP2B isoform in non-proliferating cells like cardiomyocytes is a primary driver of treatment-related cardiotoxicity [8, 13].

Other names

Topoisomerase II-DNA cleavage complexTopoisomerase II-DNA covalent complexTop2 cleavage complexTOP2-DNA complexCleavable complex

Stabilization of the topoisomerase II-DNA cleavage complex and inhibition of DNA religation, leading to permanent double-strand breaks and apoptosis.