Mechanisms Regulating Cellular Responses to DNA Topoisomerase I-Targeted Agents

Eukaryotic DNA topoisomerase I (Top1) is a conserved type IB enzyme that relaxes DNA supercoils generated during the processes of DNA replication, transcription, and recombination. The enzyme clamps around duplex DNA and forms a transient 3′ phosphotyrosyl linkage with a single DNA end. This covalent intermediate is the cellular target of the camptothecin class of chemotherapeutics, which at clinically relevant concentrations induces DNA replication-dependent lethality. Top1 is recruited to numerous protein complexes, thus CPT poisoning of Top1 induces a variety of DNA lesions. Investigations of single camptothecin (CPT)-Top1-DNA complexes with molecular tweezers suggest drug-induced accumulation of positive supercoils in advance of the replication machinery that may contribute to CPT toxicity, while recent biochemical, genetic, and genome-wide studies provide novel insights into mechanisms regulating the stability of replication forks and recombinational processing of replicative lesions in CPT-treated cells.