DNA topoisomerase 2-alpha (TOP2A)-DNA cleavable complex (TOP2A-DNA CC)

The DNA topoisomerase 2-alpha (TOP2A)-DNA cleavable complex is a transient intermediate formed during the catalytic cycle of the TOP2A enzyme, where the enzyme creates a double-strand break in DNA and becomes covalently linked to the 5' phosphate ends (UniProt: P11388). This complex is the primary pharmacological target for a class of chemotherapy agents known as topoisomerase II poisons, such as etoposide and doxorubicin (Nitiss, J. L. (2009). Nature Reviews Cancer). These drugs act by intercalating into the DNA or binding to the enzyme-DNA interface, effectively trapping the complex and preventing the religation of the DNA strands (Pommier, Y. (2013). Nature Reviews Cancer). The resulting persistence of DNA breaks overwhelms the cell's repair machinery, leading to genomic instability and the induction of programmed cell death (StatPearls: Topoisomerase Inhibitors). Because TOP2A is highly expressed in rapidly dividing cells, this complex is a critical target in the treatment of various malignancies, including lymphomas, leukemias, and solid tumors. However, the stabilization of these complexes can also lead to off-target effects, such as cardiotoxicity and the development of secondary leukemias due to chromosomal translocations (NIH: National Cancer Institute). Understanding the dynamics of this complex is essential for optimizing cancer therapies and minimizing long-term toxicities associated with topoisomerase-targeted drugs.

Other names

TOP2A-DNA covalent complexTopoisomerase II alpha-DNA cleavage complexTOP2A-DNA intermediateTOP2A-DNA binary complex

Topoisomerase II poisons stabilize the transient covalent complex formed between the TOP2A enzyme and DNA, preventing the religation of the DNA strands and leading to the accumulation of permanent double-strand breaks that trigger apoptosis (Pommier, Y. (2013). Nature Reviews Cancer).