DNA topoisomerase II–DNA covalent complex (Top2cc)

The DNA topoisomerase II–DNA covalent complex (Top2cc) is a transient catalytic intermediate formed during the action of DNA topoisomerase II, an enzyme essential for relieving torsional strain and resolving DNA catenanes during replication, transcription, and chromosome segregation (Source: PubMed, PMID: 23872618). In this complex, the enzyme creates a double-strand break and becomes covalently attached to the 5' phosphate ends of the DNA via a tyrosyl linkage (Source: UniProt, P11388). While Top2cc is normally short-lived, it is the primary target of a class of chemotherapy drugs known as topoisomerase II poisons, such as etoposide and doxorubicin (Source: StatPearls, NBK526090). These drugs stabilize the complex, preventing the religation of the DNA and effectively converting the enzyme into a source of permanent double-strand breaks (Source: PubMed, PMID: 19455154). The resulting DNA damage triggers apoptotic pathways, making Top2cc a critical focal point for treating various malignancies (Source: PubMed, PMID: 19455154). However, the stabilization of Top2cc in non-target tissues can lead to severe side effects, such as cardiotoxicity and secondary leukemias, often linked to the TOP2B isoform or chromosomal translocations (Source: PubMed, PMID: 21775456). Unlike catalytic inhibitors that prevent the complex from forming, topoisomerase poisons exploit the Top2cc to induce cell death (Source: PubMed, PMID: 23872618). Understanding the dynamics of this complex is vital for developing more selective inhibitors that minimize genomic instability in healthy cells.

Other names

Topoisomerase II cleavage complexTop2-DNA covalent complexTop2-DNA adductDNA topoisomerase 2-DNA complex

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