DNA topoisomerase II beta–DNA cleavage complex (TOP2Bcc)

The DNA topoisomerase II beta (TOP2B)–DNA cleavage complex is a transient intermediate formed during the catalytic cycle of the TOP2B enzyme, where the protein is covalently linked to the 5' ends of a double-stranded DNA break (UniProt P23511). Unlike its isoform TOP2A, which is primarily expressed in proliferating cells, TOP2B is expressed in all cell types, including quiescent cells like cardiomyocytes and neurons (Zhang et al., 2012, Nature Medicine). This complex is the primary pharmacological target for topoisomerase II poisons such as etoposide and anthracyclines, which stabilize the cleavage complex and prevent DNA religation (Nitiss, 2009, Nature Reviews Cancer). The resulting persistent double-strand breaks trigger apoptotic pathways, making these drugs effective against various cancers. However, the stabilization of TOP2Bcc in non-cancerous tissues is a major clinical concern, specifically identified as the underlying cause of anthracycline-induced cardiotoxicity (Zhang et al., 2012, Nature Medicine). Understanding the dynamics of this complex is crucial for developing more selective inhibitors that minimize off-target damage to healthy organs.

Other names

TOP2B-DNA covalent complexTopoisomerase II beta-DNA complexTOP2BccTopoisomerase IIβ-DNA cleavage complex

Stabilization of the covalent phosphotyrosyl bond between the enzyme and DNA, preventing the religation of the double-strand break and converting the enzyme into a cellular toxin (Pommier et al., 2010, Chemical Reviews).