DNA topoisomerase II – DNA cleavage complex (TOP2cc) (TOP2cc)

The DNA topoisomerase II – DNA cleavage complex (TOP2cc) is a transient, covalent intermediate formed during the catalytic cycle of type II topoisomerases, which are essential enzymes for managing DNA topology during replication, transcription, and chromosome segregation [1, 3, 8]. In this state, the homodimeric enzyme creates a double-strand break in the DNA backbone and becomes covalently attached to the resulting 5'-phosphate ends via active-site tyrosine residues [7, 8]. While normally short-lived to ensure genomic integrity, this complex is the specific molecular target for a major class of chemotherapy agents known as topoisomerase II poisons, including etoposide and anthracyclines [1, 4, 11]. These drugs stabilize the cleavage complex, preventing the religation of the DNA strands and effectively converting the enzyme into a potent cellular toxin that induces lethal double-strand breaks [4, 5, 12]. The accumulation of these stabilized complexes triggers DNA damage response pathways and apoptosis, particularly in rapidly proliferating cancer cells [5, 14]. However, the persistence of TOP2ccs can also lead to illegitimate recombination and chromosomal translocations, such as those involving the MLL gene, which are linked to the development of therapy-related secondary leukemias [3, 4, 13].

Other names

Topoisomerase II-DNA cleavage complexTOP2-DNA cleavage complexTopoisomerase II-DNA covalent complexTOP2-DNA adductTernary topoisomerase II-DNA-drug complex

Stabilization of the transient covalent enzyme-DNA intermediate to prevent DNA religation, leading to the accumulation of double-strand breaks and induction of apoptosis.