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

The DNA–topoisomerase II alpha complex is a transient intermediate formed during the catalytic cycle of the topoisomerase II alpha (TOP2A) enzyme, where the enzyme is covalently linked to DNA via a phosphotyrosyl bond (UniProt P11388). This complex is essential for managing DNA topology during critical cellular processes such as DNA replication, transcription, and chromosome segregation by facilitating the passage of one DNA double helix through another via a temporary double-strand break (Nitiss, 2009). In many cancer types, TOP2A is significantly overexpressed to support rapid cell proliferation, making the DNA-enzyme complex a primary target for chemotherapy (Pommier et al., 2010). Drugs known as topoisomerase II poisons, including etoposide and doxorubicin, act by binding to and stabilizing this cleavage complex, preventing the enzyme from resealing the DNA breaks (StatPearls, 2023). This stabilization leads to the accumulation of permanent double-strand breaks, which ultimately triggers programmed cell death (apoptosis) in tumor cells (PubMed, PMID: 19373244). However, targeting this complex can lead to significant side effects, such as cardiotoxicity and the risk of secondary malignancies like treatment-related leukemia (DrugBank, DB00773).

Other names

DNA-topoisomerase IIα cleavage complexTOP2A-DNA complexTopoisomerase II alpha-DNA covalent complexTOP2AccDNA topoisomerase 2-alpha–DNA complex

Stabilization of the covalent DNA-enzyme cleavage complex, preventing DNA religation and inducing lethal double-strand breaks.