Cellular Responses to DNA Damage Induced by Topoisomerase Poisons

DNA topoisomerase I is an abundant nuclear enzyme that adjusts the torsional strain on DNA during processes such as replication and transcription. This enzyme is also the target for the anticancer drugs irinotecan and topotecan, which are active in a variety of solid tumors, including cancers of the colon, pancreas, lung and ovary. Studies in our laboratory are examining factors that potentially affect the ability of these drugs to inhibit topoisomerase I (drug uptake and posttranslational modifications of topoisomerase I) as well as cellular responses to drug-induced trapping of covalent topoisomerase I-DNA complexes. Based on our earlier studies showing that inactivation of the ATR/Chk1 pathway sensitizes cells to killing by this class of agents, we are also currently investigating how topoisomerase I poisons activate this DNA damage response pathway.