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

The DNA topoisomerase II alpha-DNA cleavage complex (TOP2A-cc) is a transient, covalent intermediate formed during the catalytic cycle of the enzyme DNA topoisomerase II alpha (TOP2A) [1, 11]. In this state, the enzyme creates a double-strand break in the DNA (the G-segment) and remains covalently linked to the 5' ends of the DNA via active-site tyrosine residues [4, 9]. This complex is the primary therapeutic target of topoisomerase poisons such as etoposide, teniposide, and doxorubicin, which stabilize the complex and prevent the religation of the DNA strands [2, 3, 12]. The persistence of these complexes leads to permanent double-strand breaks when replication or transcription machinery collides with the trapped enzyme, ultimately triggering apoptosis in rapidly dividing cancer cells [8, 10]. While these drugs are effective chemotherapeutic agents, the stabilization of TOP2A-cc can also lead to illegitimate DNA repair and chromosomal translocations, which are associated with the development of secondary malignancies, such as therapy-related acute myeloid leukemia [7, 13, 14].

Other names

TOP2A-ccTOP2A-DNA cleavage complexTOP2A-DNA protein crosslinkTOP2A-DPCCleavable complexDNA topoisomerase 2-alpha cleavage complex

Topoisomerase II poisons stabilize the covalent DNA-protein intermediate, known as the cleavage complex, by inhibiting the religation of the double-strand DNA break [2, 3]. This stabilization leads to the accumulation of transient breaks that are converted into permanent, cytotoxic double-strand breaks upon collision with DNA tracking enzymes like RNA polymerase or DNA polymerase [8, 12]. The resulting DNA damage overwhelms the cell's repair capacity and triggers programmed cell death [10, 13].