DNA-DNA topoisomerase 2-alpha cleavage complex (TOP2Acc) (TOP2Acc)

The DNA-DNA topoisomerase 2-alpha cleavage complex (TOP2Acc) is a transient, covalent intermediate formed during the catalytic cycle of the DNA topoisomerase 2-alpha (TOP2A) enzyme. In this state, the enzyme creates a double-strand break in the DNA phosphodiester backbone and becomes covalently attached to the 5' ends of the DNA via tyrosine residues (Pommier et al., 2010, PubMed: 20102561). This complex is vital for cellular processes such as DNA replication, transcription, and chromosome segregation, as it allows the enzyme to pass a second DNA duplex through the break to resolve knots and tangles (Nitiss, 2009, PubMed: 19448666). Because TOP2A expression is tightly linked to cell proliferation, this complex is a primary target for several classes of anticancer drugs known as topoisomerase II poisons, including epipodophyllotoxins like etoposide and anthracyclines like doxorubicin (Deweese & Osheroff, 2009, PubMed: 18711101). These drugs act by binding to the cleavage complex and inhibiting the re-ligation of the DNA strands, effectively trapping the enzyme on the DNA. The resulting accumulation of protein-linked double-strand breaks triggers the DNA damage response and leads to programmed cell death (apoptosis) (UniProt: P11388). While effective, these therapies are associated with severe side effects, most notably myelosuppression and a risk of therapy-related secondary malignancies, such as acute myeloid leukemia, due to the induction of chromosomal translocations (StatPearls, 2023). Additionally, cardiotoxicity is a significant concern with anthracyclines, often attributed to off-target effects on the related topoisomerase II beta isoform in cardiomyocytes.

Other names

TOP2A-DNA complexTopoisomerase II alpha-DNA covalent complexDNA-TOP2A cleavage complexTopoisomerase II alpha cleavage complex

Stabilization of the covalent DNA-protein intermediate (cleavage complex), inhibiting DNA re-ligation and inducing lethal double-strand breaks.