DNA topoisomerase 1-DNA covalent complex (Top1cc) (Top1cc)

The DNA topoisomerase 1-DNA covalent complex (Top1cc) is a transient catalytic intermediate formed when the Topoisomerase I enzyme (UniProt: P11387) cleaves a single strand of the DNA double helix to relieve torsional strain. During this process, the enzyme becomes covalently attached to the 3' phosphate end of the DNA via a tyrosine residue (Pommier, Nat Rev Cancer, 2006). Under normal conditions, this complex is rapidly resolved as the enzyme religates the DNA; however, it becomes a lethal lesion when stabilized by therapeutic agents. Drugs such as irinotecan and topotecan act as interfacial inhibitors, trapping the Top1cc and preventing the religation step (PubMed: 16446761). When DNA replication forks or transcription machinery collide with these trapped complexes, the single-strand breaks are converted into permanent, cytotoxic double-strand breaks (Thomas & Pommier, Clin Cancer Res, 2019). This mechanism is primarily utilized in oncology to target rapidly dividing cancer cells that have high rates of DNA replication. The repair of Top1cc is mediated by enzymes like Tyrosyl-DNA phosphodiesterase 1 (TDP1), and the expression of Schlafen 11 (SLFN11) has emerged as a critical biomarker for predicting sensitivity to Top1-targeted therapies (Zoppoli et al., PNAS, 2012). Consequently, the Top1cc is not just an enzyme intermediate but a distinct pharmacological target whose persistence determines the efficacy of several frontline chemotherapeutic regimens.

Other names

Top1ccTop1 cleavage complexTopoisomerase I-DNA cleavage complexTop1-DNA adductTopoisomerase I-DNA intermediate

Interfacial inhibition by binding at the DNA-enzyme interface to stabilize the covalent complex and prevent DNA religation (Pommier, Nat Rev Cancer, 2006).