DNA topoisomerase II beta cleavage complex (TOP2Bcc)

DNA topoisomerase II beta (TOP2B) is a ubiquitous enzyme that manages DNA topology by creating transient double-strand breaks to allow the passage of one DNA duplex through another [7, 13]. The DNA topoisomerase II beta cleavage complex (TOP2Bcc) is the catalytic intermediate in which the enzyme is covalently bound to the 5' ends of the DNA backbone via phosphotyrosyl bonds [16, 18, 22]. This complex is the primary target of topoisomerase II poisons, such as etoposide and anthracyclines, which stabilize the complex and prevent the religation of DNA [1, 4, 16]. While this mechanism is exploited to kill cancer cells, the presence of TOP2B in non-dividing cells like cardiomyocytes makes the TOP2Bcc a primary mediator of drug-induced cardiotoxicity [5, 6, 10, 15]. Furthermore, the stabilization of TOP2Bcc can lead to illegitimate DNA repair and chromosomal translocations, which are associated with secondary malignancies like acute myeloid leukemia [2, 16, 18]. Understanding the TOP2Bcc is therefore critical for both enhancing chemotherapeutic efficacy and mitigating severe off-target toxicities [15, 17].

Other names

TOP2B cleavage complexTopoisomerase II beta-DNA complexTOP2B-DNA covalent complexTOP2B-DNA phosphotyrosyl complexCleavable complex

Topoisomerase II poisons stabilize the covalent cleavage complex by inhibiting the religation of DNA double-strand breaks, effectively converting the enzyme into a cellular toxin that induces apoptosis [1, 4, 16, 18].