We have attempted to use a familial genetics strategy to study mechanisms of Topoisomerase 1 (Top1) inhibition. Investigations have steadily been chipping away at the pathways involved in cellular response following Top1 inhibition for more than 20 years. Our system-wide approach, which phenotypes a collection of genotyped human cell lines for sensitivity to compounds, interrogates all genes and molecular pathways simultaneously. Previously, we characterized the in vitro sensitivity of fifteen families of CEPH cell lines (n = 142) to nine camptothecin analogues. Linkage analysis revealed a pattern of seven quantitative trait loci (QTLs) shared by all of the camptothecins. To identify which, if any, QTLs are related to the general mechanism of Top1 inhibition or should be considered camptothecin-specific, we characterized the in vitro sensitivity of the same panel of CEPH cell lines to the indenisoquinolones, a structurally distinct class of Top 1 inhibitors. Four QTLs on chromosomes 1, 5, 11, and 16 were shared by both the camptothecins and the indenoisoquinolines and are considered associated with the general mechanism of Top1 inhibition. The remaining three QTLs (chromosomes 6 and 20) are considered specific to camptothecin-induced cytotoxicity. Finally, eight QTLs were identified which were unique to the indenoisoquinolines.
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