High-throughput screening for genes that prevent excess DNA replication in human cells and for molecules that inhibit them.
High-throughput screening for genes that prevent excess DNA replication in human cells and for molecules that inhibit them.
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DOI：
10.1016/j.ymeth.2012.03.031
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发表时间：
2012-06
期刊：
影响因子：
4.8
通讯作者：
DePamphilis, Melvin L.
中科院分区：
文献类型：
--
作者：
Lee, Chrissie Y.;Johnson, Ronald L.;Wichterman-Kouznetsova, Jennifer;Guha, Rajarshi;Ferrer, Marc;Tuzmen, Pinar;Martin, Scott E.;Zhu, Wenge;DePamphilis, Melvin L.
关键词：
高通量筛选（HTS）提供了一种快速而全面的方法来鉴定靶向特定生物过程以及这些过程所必需的基因的化合物。在这里，我们描述了一种HTS测定法，用于在源自人类癌症的细胞中选择性诱导DNA再复制或核内复制（即过量DNA复制）的小分子。这些分子不仅可用于研究细胞分裂和分化，而且可能为癌症化疗提供新的方法。由于诱导DNA重新复制会导致细胞凋亡，因此选择性诱导癌细胞中DNA重新复制而不在正常细胞中这样做的化合物可以在体内杀死癌症，而不会阻止正常细胞增殖。此外，相同的HTS测定可适于筛选siR-NA分子以鉴定其产物将基因组复制限制为每次细胞分裂一次的基因。这些基因中的一些可能在正常人类发育期间调节终末分化的多倍体细胞的形成，而另一些则会在每次细胞分裂期间阻止DNA再复制。基于以前的研究，我们预计，一个或多个后者的基因将被证明是必不可少的癌细胞的增殖，但不是正常细胞，因为许多癌细胞是缺乏维持基因组稳定性的机制。
High-throughput screening (HTS) provides a rapid and comprehensive approach to identifying compounds that target specific biological processes as well as genes that are essential to those processes. Here we describe a HTS assay for small molecules that induce either DNA re-replication or endoreduplication (i.e. excess DNA replication) selectively in cells derived from human cancers. Such molecules will be useful not only to investigate cell division and differentiation, but they may provide a novel approach to cancer chemotherapy. Since induction of DNA re-replication results in apoptosis, compounds that selectively induce DNA re-replication in cancer cells without doing so in normal cells could kill cancers in vivo without preventing normal cell proliferation. Furthermore, the same HTS assay can be adapted to screen siR-NA molecules to identify genes whose products restrict genome duplication to once per cell division. Some of these genes might regulate the formation of terminally differentiated polyploid cells during normal human development, whereas others will prevent DNA re-replication during each cell division. Based on previous studies, we anticipate that one or more of the latter genes will prove to be essential for proliferation of cancer cells but not for normal cells, since many cancer cells are deficient in mechanisms that maintain genome stability.
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影响因子：
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