Inhibition of Homologous Recombination in Human Cells by Targeting RAD51 Recombinase
Inhibition of Homologous Recombination in Human Cells by Targeting RAD51 Recombinase
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DOI：
10.1021/jm201173g
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发表时间：
2012-04-12
影响因子：
7.3
通讯作者：
Mazin, Alexander V.
中科院分区：
文献类型：
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作者：
Huang, Fei;Mazina, Olga M.;Mazin, Alexander V.
同源重组（HR）途径在DNA双链断裂（DSB）和链间交联（ICL）的修复中起着至关重要的作用。RAD51是HR的关键蛋白，具有独特的活性：同源DNA序列之间的DNA链交换。最近，使用高通量筛选（HTS），我们鉴定了化合物1（B02），其特异性抑制人RAD 51的DNA链交换活性。在这里，我们分析了抑制机制，发现1破坏了RAD 51与DNA的结合。然后，我们检查了1对细胞中HR和DNA修复的影响。结果表明，1抑制HR并增加细胞对DNA损伤的敏感性。我们建议使用1来分析RAD 51的细胞功能。由于DSB和ICL诱导剂常用于抗癌治疗，因此RAIDS 1的特异性抑制剂也可能有助于增加对癌细胞的杀伤。
The homologous recombination (HR) pathway plays a crucial role in the repair of DNA double-strand breaks (DSBs) and interstrand cross-links (ICLs). RAD51, a key protein of HR, possesses a unique activity: DNA strand exchange between homologous DNA sequences. Recently, using a high-throughput screening (HTS), we identified compound 1 (B02), which specifically inhibits the DNA strand exchange activity of human RAD51. Here, we analyzed the mechanism of inhibition and found that 1 disrupts RAD51 binding to DNA. We then examined the effect of 1 on HR and DNA repair in the cell. The results show that 1 inhibits HR and increases cell sensitivity to DNA damage. We propose to use 1 for analysis of cellular functions of RAD51. Because DSB- and ICL-inducing agents are commonly used in anticancer therapy, specific inhibitors of RAIDS 1 may also help to increase killing of cancer cells.