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

DNA topoisomerase II alpha (TOP2A) is an essential nuclear enzyme that regulates DNA topology by generating transient double-strand breaks, allowing the passage of one DNA duplex through another to resolve knots and tangles [1]. The TOP2A-DNA cleavage complex represents a critical catalytic intermediate where the enzyme is covalently bound to the 5' ends of the cleaved DNA via a phosphotyrosyl bond [2]. This complex is the primary target for several classes of potent anticancer drugs, collectively known as topoisomerase II poisons, which act by stabilizing this intermediate and preventing the religation of the DNA backbone [3]. The resulting accumulation of stabilized cleavage complexes leads to the formation of permanent DNA double-strand breaks when the cell attempts to replicate or transcribe the affected DNA [4]. Because TOP2A is highly expressed in rapidly dividing cells, it is a major therapeutic target for treating various malignancies, including breast cancer, lung cancer, and lymphomas [5]. However, the stabilization of these complexes in non-target tissues can lead to significant adverse effects, such as cardiotoxicity and the development of secondary leukemias due to chromosomal translocations [6].

Other names

Topoisomerase II alpha-DNA complexTOP2A-DNA covalent complexDNA topoisomerase 2-alpha-DNA complexTOP2A cleavage complex

Topoisomerase II poisons stabilize the transient covalent complex formed between the enzyme and DNA (the cleavage complex), preventing the religation of DNA strands and leading to the accumulation of permanent double-strand breaks, which triggers apoptosis [3, 4].