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

DNA topoisomerase 2-alpha (TOP2A) is a critical nuclear enzyme that regulates the topological state of DNA during essential cellular processes such as replication, transcription, and chromosome segregation (UniProt: P11388). It functions by creating transient double-strand breaks in the DNA phosphodiester backbone, passing a second DNA duplex through the break, and subsequently religating the strands (PubMed: 19143604). The "cleavable complex" refers to the short-lived intermediate state where the enzyme is covalently bonded to the 5' ends of the cleaved DNA (StatPearls: Topoisomerase Inhibitors). This complex is the primary pharmacological target for a class of chemotherapy agents known as topoisomerase II poisons, including etoposide and anthracyclines (PubMed: 23849032). These drugs act by stabilizing the cleavable complex, preventing the religation of DNA and leading to the accumulation of permanent double-strand breaks. The resulting genomic instability and DNA damage overwhelm the cell's repair machinery, ultimately triggering programmed cell death (apoptosis). Because TOP2A is highly expressed in rapidly proliferating cells, it is a major target in the treatment of various malignancies, including leukemias, lymphomas, and solid tumors like breast and lung cancer (NCBI: PMC3070693). However, targeting this complex is associated with significant side effects, most notably dose-limiting cardiotoxicity and the risk of secondary treatment-related leukemias (PubMed: 11331020).

Other names

TOP2A-DNA complexTopoisomerase II alpha-DNA covalent complexTopoisomerase II alpha-DNA cleavage complexTOP2A-DNA phosphotyrosyl complex

Stabilization of the covalent TOP2A-DNA cleavage intermediate (cleavable complex), inhibition of DNA religation, and induction of lethal double-strand DNA breaks (PubMed: 19143604).