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

The "TOP2A–DNA complex" refers specifically to the transient, covalent enzyme–DNA cleavage intermediate formed by DNA topoisomerase 2-alpha (TOP2A) during its catalytic cycle[1][2][4]. TOP2A is a homodimeric nuclear enzyme essential for resolving overwound or tangled DNA during replication, transcription, and chromosome segregation[1][2][7]. The enzyme operates by binding to double-stranded DNA, introducing a staggered double-strand break, and forming a covalent phosphotyrosyl bond with the 5′ ends at the break (the cleavage complex), allowing passage of a second DNA helix before re-ligating the break[2][4]. Many anticancer drugs—especially the anthracyclines (doxorubicin, daunorubicin, etc.) and epipodophyllotoxins (etoposide, teniposide)—exploit this mechanism by stabilizing the cleavage complex, thus inhibiting DNA religation and inducing persistent double-strand breaks, which are cytotoxic to proliferating cancer cells[1][4][5][7]. This complex is a major therapeutic target in oncology because it is the primary action site of "TOP2 poisons." However, trapping of the complex also underlies safety concerns, notably secondary malignancies and myelosuppression[4][6]. Mutations or alterations in TOP2A may confer drug resistance or serve as cancer biomarkers[3][5][6]. Note: The "TOP2A–DNA complex" is not a standalone molecule but a transient catalytic intermediate formed between the enzyme and its DNA substrate. The correct therapeutic target is "DNA topoisomerase 2-alpha" (TOP2A) itself[1][2][7]. Therefore, this entry is considered incorrect as a canonical drug target name but accurate for describing the drug–enzyme–DNA interaction underlying the mechanism of many anti-cancer drugs.

Other names

Topoisomerase IIα–DNA complexTOP2A cleavage complexTOP2AccTOP2A–cleaved DNA complex

Stabilization of the TOP2A–DNA covalent cleavage complex (leading to irreversible DNA double-strand breaks), Enzymatic inhibition (preventing religation of DNA), Enzyme poisoning, Allosteric inhibition