Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel.
Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel.
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DOI：
10.1158/1535-7163.mct-13-0551
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发表时间：
2014-01
影响因子：
5.7
通讯作者：
Murai J
中科院分区：
文献类型：
--
作者：
Maede Y;Shimizu H;Fukushima T;Kogame T;Nakamura T;Miki T;Takeda S;Pommier Y;Murai J
临床拓扑异构酶 I (Top1) 和 II (Top2) 抑制剂可捕获 DNA 上的拓扑异构酶，从而诱导蛋白连接的 DNA 断裂。 Cancer cells resist the drugs by removing topoisomerase-DNA complexes, and repairing the drug-induced DNA double-strand breaks (DSBs) by homologous recombination (HR) and non-homologous end-joining (NHEJ). Because numerous enzymes and cofactors are involved in the removal of the topoisomerase-DNA complexes and DSB repair, it has been challenging to comprehensively analyze the relative contribution of multiple genetic pathways in vertebrate cells. Comprehending the relative contribution of individual repair factors would give insights into the lesions induced by the inhibitors and genetic determinants of response.最终，这些信息将有助于针对特定途径来增强拓扑异构酶抑制剂的治疗活性。为此，我们将 48 个缺乏 DNA 修复的同基因 DT40 突变细胞放在一起，并产生了一个缺乏自噬的细胞系 (ATG5)。 Sensitivity profiles were established for three clinically relevant Top1 inhibitors (camptothecin and the indenoisoquinolines LMP400 and LMP776) and three topoisomerase II inhibitors (etoposide, doxorubicin and ICRF-193). Highly significant correlations were found among Top1 inhibitors as well as Top2 inhibitors, while the profiles of Top1 inhibitors were different from those of Top2 inhibitors. Most distinct repair pathways between Top1 and Top2 inhibitors include NHEJ, TDP1, TDP2, PARP1 and Fanconi Anemia genes whereas HR appears relevant especially for Top1 and to a lesser extent for Top2 inhibitors.我们还发现并讨论了 Top1 抑制剂和 Top2 抑制剂之间的差异途径。
Clinical topoisomerase I (Top1) and II (Top2) inhibitors trap topoisomerases on DNA, thereby inducing protein-linked DNA breaks. Cancer cells resist the drugs by removing topoisomerase-DNA complexes, and repairing the drug-induced DNA double-strand breaks (DSBs) by homologous recombination (HR) and non-homologous end-joining (NHEJ). Because numerous enzymes and cofactors are involved in the removal of the topoisomerase-DNA complexes and DSB repair, it has been challenging to comprehensively analyze the relative contribution of multiple genetic pathways in vertebrate cells. Comprehending the relative contribution of individual repair factors would give insights into the lesions induced by the inhibitors and genetic determinants of response. Ultimately, this information would be useful to target specific pathways to augment the therapeutic activity of topoisomerase inhibitors. To this end, we put together 48 isogenic DT40 mutant cells deficient in DNA repair and generated one cell line deficient in autophagy (ATG5). Sensitivity profiles were established for three clinically relevant Top1 inhibitors (camptothecin and the indenoisoquinolines LMP400 and LMP776) and three topoisomerase II inhibitors (etoposide, doxorubicin and ICRF-193). Highly significant correlations were found among Top1 inhibitors as well as Top2 inhibitors, while the profiles of Top1 inhibitors were different from those of Top2 inhibitors. Most distinct repair pathways between Top1 and Top2 inhibitors include NHEJ, TDP1, TDP2, PARP1 and Fanconi Anemia genes whereas HR appears relevant especially for Top1 and to a lesser extent for Top2 inhibitors. We also found and discuss differential pathways among Top1 inhibitors and Top2 inhibitors.