Fig. 4

A schematic illustrating replication fork arrest by a drug-aborted topoisomerase I-DNA cleavable complex. In this model, the camptothecin trapped topoisomerase I-DNA cleavable complex is viewed as a bulky DNA lesion which arrests the replication fork by blocking the movement of replication machinery. This blockage also alters the physical state of the cleavable complex and possibly leads to fork breakage at the complex site. At low levels of cleavable complexes, when only one replication fork is arrested, continued replication by the other unimpeded fork on the same plasmid DNA leads to the formation of linearized replication products. The irreversible replication arrest and fork breakage may be the cause of camptothecin’s S-phase-specific cytotoxicity [62, 63]