DNA topoisomerase 1-DNA cleavage complex (TOP1cc)

DNA topoisomerase 1 (TOP1) is a vital nuclear enzyme that regulates DNA topology by creating transient single-strand breaks to relieve torsional strain during replication and transcription (UniProt P11387). The Topoisomerase I – DNA cleavage complex (TOP1cc) is the specific catalytic intermediate where the enzyme is covalently linked to the 3' end of the DNA (Pommier, Nat Rev Cancer 2006). This complex is the primary pharmacological target for camptothecin derivatives and indenoisoquinolines, which act as interfacial inhibitors by binding at the DNA-enzyme interface (Thomas et al., Chem Rev 2004). By stabilizing the TOP1cc, these drugs prevent the religation of the DNA strand, leading to the formation of lethal double-strand breaks when the complex is encountered by replication forks (Murai et al., Cancer Res 2012). This mechanism is highly effective in treating various malignancies, including colorectal and small-cell lung cancers, although its clinical utility is often limited by toxicities such as severe myelosuppression and gastrointestinal distress (StatPearls, Irinotecan). Cellular resistance can also arise through the upregulation of repair enzymes like Tyrosyl-DNA phosphodiesterase 1 (TDP1), which can excise the trapped TOP1 from the DNA (Pommier, Nat Rev Cancer 2006).

Other names

TOP1-DNA covalent complexTopoisomerase I-DNA complexTOP1 cleavage complexDNA topoisomerase 1 (TOP1)

Interfacial inhibition that stabilizes the transient covalent TOP1-DNA cleavage complex, preventing DNA religation and causing replication fork collapse into lethal double-strand breaks.