DNA topoisomerase I-DNA cleavable complex (TOP1cc)

The DNA topoisomerase I-DNA cleavable complex (TOP1cc) is a transient catalytic intermediate formed during the relaxation of DNA supercoiling (6, 20). In this complex, the DNA topoisomerase I (TOP1) enzyme is covalently linked to the 3-prime-phosphate end of a single-strand DNA break via a catalytic tyrosine residue (12, 16). This intermediate is essential for relieving torsional strain during critical cellular processes such as DNA replication and transcription (19, 20). However, the TOP1cc is also the primary molecular target for a class of anticancer agents known as TOP1 poisons, including camptothecin and its derivatives like irinotecan and topotecan (1, 11). These drugs act as interfacial inhibitors, binding at the junction of the enzyme and DNA to stabilize the complex and prevent the religation of the DNA strand (7, 16). The persistence of these trapped complexes leads to collisions with advancing replication forks, transforming single-strand nicks into irreversible double-strand breaks that trigger apoptosis (2, 6). Consequently, TOP1cc stabilization is a potent strategy for treating various malignancies, including colorectal, ovarian, and small cell lung cancers, although it is associated with significant toxicities such as myelosuppression and severe diarrhea (3, 15, 21).

Other names

Top1-DNA covalent complexTop1-DNA cleavage complexTop1-DNA intermediateTop1-DNA adductTopoisomerase I-DNA complex

Interfacial inhibition by stabilizing the transient covalent DNA topoisomerase I-DNA complex, preventing the religation of the DNA strand and leading to lethal double-strand breaks upon collision with replication forks.