DNA topoisomerase II alpha–DNA cleavage complex (TOP2A-DNA CC)

DNA topoisomerase II alpha (TOP2A) is a vital nuclear enzyme that manages DNA topology by inducing transient double-strand breaks to resolve knots and supercoils during replication and mitosis (UniProt: P11388). The DNA topoisomerase II alpha–DNA cleavage complex is a specific catalytic intermediate where the enzyme is covalently linked to the DNA backbone (PubMed: 19151755). This complex is the primary pharmacological target for topoisomerase II poisons, such as etoposide and doxorubicin, which act by stabilizing the complex and preventing the re-ligation of DNA strands (StatPearls: NBK526090). The stabilization of these complexes leads to the accumulation of permanent double-strand breaks, which triggers the DNA damage response and ultimately results in apoptosis (PubMed: 23875711). Because TOP2A is highly expressed in rapidly proliferating cells, it is a major target in the treatment of various cancers, including leukemias and solid tumors (PubMed: 11738237). However, the use of drugs targeting this complex is associated with significant risks, such as dose-limiting cardiotoxicity and the development of secondary malignancies like acute myeloid leukemia (PubMed: 15064665). Monitoring TOP2A expression levels and gene amplification can serve as a biomarker for predicting treatment efficacy in certain patient populations (PubMed: 21558517).

Other names

TOP2A-DNA covalent complexTopoisomerase II alpha-DNA complexTOP2A cleavage complexDNA topoisomerase 2-alpha

Stabilization of the transient covalent DNA-protein intermediate (cleavage complex), preventing DNA re-ligation and inducing lethal double-strand breaks (PubMed: 19151755).