DNA topoisomerase 2-DNA covalent complex (Top2cc) (Top2cc)

The DNA topoisomerase 2-DNA covalent complex, also known as the Top2 cleavage complex (Top2cc), is a critical catalytic intermediate where the topoisomerase II enzyme is covalently linked to DNA via a phosphotyrosyl bond (Pommier et al., 2016). Under normal conditions, this complex is short-lived, facilitating the passage of one DNA duplex through another to manage DNA topology during replication, transcription, and chromosome segregation (Nitiss, 2009). However, many potent anticancer drugs, termed topoisomerase II poisons, act by binding to and stabilizing this complex, preventing the religation of the DNA double-strand break (Deweese & Osheroff, 2009). This stabilization leads to the accumulation of permanent DNA damage when the complex encounters replication forks or transcription machinery, ultimately triggering programmed cell death (Pommier et al., 2016). While these drugs are staples in oncology, their interaction with the Topo IIβ isoform in non-dividing cells is a primary driver of dose-limiting cardiotoxicity (Zhang et al., 2012). Furthermore, the persistence of these complexes can lead to chromosomal translocations, increasing the risk of secondary malignancies such as acute myeloid leukemia (Nitiss, 2009). Consequently, the Top2cc represents a unique therapeutic target where the drug's efficacy is derived from the stabilization of a normally transient enzyme-DNA state rather than simple inhibition of enzymatic activity.

Other names

Topoisomerase II cleavage complexTopo II-DNA adductTIICCTop2-DNA covalent complex

Stabilization of the covalent enzyme-DNA intermediate (cleavage complex), preventing DNA religation and inducing double-strand breaks.