RECQL1 and WRN DNA repair helicases: potential therapeutic targets and proliferative markers against cancers.
RECQL1 and WRN DNA repair helicases: potential therapeutic targets and proliferative markers against cancers.
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DOI：
10.3389/fgene.2014.00441
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发表时间：
2014
影响因子：
3.7
通讯作者：
Furuichi Y
中科院分区：
文献类型：
--
作者：
Futami K;Furuichi Y
人RecQ解旋酶家族中的RECQL 1和WRN解旋酶参与维持细胞周期中的基因组稳定性、DNA修复、复制和重组途径。它们在快速增殖的细胞和肿瘤细胞中高度表达，表明它们在基因组的复制中具有重要作用。尽管缺乏这些解旋酶的小鼠与野生型小鼠无法区分，但它们的胚胎成纤维细胞对DNA损伤敏感。在肿瘤细胞中，通过RNA干扰沉默RECQL 1或WRN解旋酶的表达诱导有丝分裂灾难，最终在细胞周期的有丝分裂阶段杀死肿瘤细胞。相比之下，同源小RNA（siRNA）的相同基因沉默不会杀死正常细胞，尽管细胞生长略有延迟。这些发现表明RECQL 1和WRN解旋酶是癌症治疗的理想分子靶点。这些事件背后的分子机制已被广泛研究，这可能有助于通过靶向DNA修复解旋酶RECQL 1和WRN开发无不良反应的抗癌药物。正如预期的那样，常规遗传毒性药物的抗癌活性通过与RECQL 1或WRN-siRNA的联合治疗显著增强，这会阻止癌细胞中的DNA修复。在这篇综述中，我们专注于阐明导致特异性杀伤癌细胞的机制的研究，并介绍了开发无不良反应的抗癌RecQ-siRNA药物的努力。
RECQL1 and WRN helicases in the human RecQ helicase family participate in maintaining genome stability, DNA repair, replication, and recombination pathways in the cell cycle. They are expressed highly in rapidly proliferating cells and tumor cells, suggesting that they have important roles in the replication of a genome. Although mice deficient in these helicases are indistinguishable from wild-type mice, their embryonic fibroblasts are sensitive to DNA damage. In tumor cells, silencing the expression of RECQL1 or WRN helicase by RNA interference induces mitotic catastrophe that eventually kills tumor cells at the mitosis stage of the cell cycle. By contrast, the same gene silencing by cognate small RNA (siRNA) never kills normal cells, although cell growth is slightly delayed. These findings indicate that RECQL1 and WRN helicases are ideal molecular targets for cancer therapy. The molecular mechanisms underlying these events has been studied extensively, which may help development of anticancer drugs free from adverse effects by targeting DNA repair helicases RECQL1 and WRN. As expected, the anticancer activity of conventional genotoxic drugs is significantly augmented by combined treatment with RECQL1- or WRN-siRNAs that prevents DNA repair in cancer cells. In this review, we focus on studies that clarified the mechanisms that lead to the specific killing of cancer cells and introduce efforts to develop anticancer RecQ-siRNA drugs free from adverse effects.