Halenaquinone, a chemical compound that specifically inhibits the secondary DNA binding of RAD51
Halenaquinone, a chemical compound that specifically inhibits the secondary DNA binding of RAD51
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DOI：
10.1111/j.1365-2443.2011.01494.x
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发表时间：
2011-04-01
期刊：
影响因子：
2.1
通讯作者：
Kurumizaka, Hitoshi
中科院分区：
文献类型：
--
作者：
Takaku, Motoki;Kainuma, Takashi;Kurumizaka, Hitoshi
突变和单核苷酸多态性影响RAD 51基因功能已被确定在几种肿瘤，表明RAD 51活性的不适当表达可能会导致肿瘤发生。RAD 51是DNA双链断裂同源重组修复（HRR）的必需酶。在HRR途径中，RAD 51催化单链DNA（ssDNA）和双链DNA（dsDNA）之间的同源配对，这是HRR途径的中心步骤。为了鉴定调节RAD 51同源配对活性的化合物，在本研究中，我们通过RAD 51介导的同源配对测定筛选了海绵粗提物组分。Halenaquinone被鉴定为RAD 51同源配对活性的抑制剂。表面等离子体共振分析表明，halenaquinone直接结合到RAD 51。有趣的是，卤醌特异性抑制单独的RAD 51或RAD 51-ssDNA复合物与dsDNA的结合，但对RAD 51-ssDNA结合的影响很弱。在体内，halenaquinone显着抑制双链断裂位点的RAD 51的保留。因此，卤醌是一种新型的特异性抑制RAD 51-dsDNA结合的RAD 51抑制剂。
Mutations and single-nucleotide polymorphisms affecting RAD51 gene function have been identified in several tumors, suggesting that the inappropriate expression of RAD51 activity may cause tumorigenesis. RAD51 is an essential enzyme for the homologous recombinational repair (HRR) of DNA double-strand breaks. In the HRR pathway, RAD51 catalyzes the homologous pairing between single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), which is the central step of the HRR pathway. To identify a chemical compound that regulates the homologous-pairing activity of RAD51, in the present study, we screened crude extract fractions from marine sponges by the RAD51-mediated homologous-pairing assay. Halenaquinone was identified as an inhibitor of the RAD51 homologous-pairing activity. A surface plasmon resonance analysis indicated that halenaquinone directly bound to RAD51. Intriguingly, halenaquinone specifically inhibited dsDNA binding by RAD51 alone or the RAD51-ssDNA complex, but only weakly affected the RAD51-ssDNA binding. In vivo, halenaquinone significantly inhibited the retention of RAD51 at double-strand break sites. Therefore, halenaquinone is a novel type of RAD51 inhibitor that specifically inhibits the RAD51-dsDNA binding.