DNA–topoisomerase II beta cleavable complex (DNA–TOP2B CC)

The DNA–topoisomerase II beta (TOP2B) cleavable 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 P23122). Unlike its isoform TOP2A, which is primarily involved in DNA replication, TOP2B is expressed throughout the cell cycle and plays a critical role in regulating transcription and chromatin architecture, particularly in post-mitotic cells like neurons and cardiomyocytes (Nitiss, Nat Rev Cancer, 2009). This complex is the primary pharmacological target of topoisomerase II poisons, such as etoposide and anthracyclines, which stabilize the complex and prevent DNA religation. The resulting accumulation of DNA double-strand breaks leads to cell death, making it a potent mechanism for chemotherapy (StatPearls, Topoisomerase Inhibitors). However, the stabilization of TOP2B cleavable complexes in non-cancerous tissues is a major driver of clinical side effects, most notably the cardiotoxicity associated with anthracycline use (Zhang et al., Nat Med, 2012). Understanding the specific dynamics of this complex is essential for developing more selective inhibitors that minimize off-target damage to healthy organs.

Other names

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

Topoisomerase II poisons stabilize the transient covalent complex between the enzyme and DNA, preventing the religation of the DNA strands and leading to the accumulation of permanent double-strand breaks that trigger apoptosis (Nitiss, Nat Rev Cancer, 2009).