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Halenaquinone, a chemical compound that specifically inhibits the secondary DNA binding of RAD51

机译：Halenaquinone，一种化合物，可特异性抑制RAD51的次级DNA结合

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摘要

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.
机译：已经在几种肿瘤中发现了影响RAD51基因功能的突变和单核苷酸多态性，这表明RAD51活性的不适当表达可能引起肿瘤发生。 RAD51是DNA双链断裂的同源重组修复（HRR）的必需酶。在HRR途径中，RAD51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RAD51同源配对活性的化合物，在本研究中，我们通过RAD51介导的同源配对分析从海洋海绵中筛选了粗提物级分。 Halenaquinone被确定为RAD51同源配对活性的抑制剂。表面等离子体共振分析表明，卤代醌直接结合到RAD51。有趣的是，卤代醌可以单独抑制RAD51或RAD51-ssDNA复合物对dsDNA的结合，但对RAD51-ssDNA结合的影响很小。在体内，卤代醌显着抑制了RAD51在双链断裂位点的保留。因此，卤代醌是一种新型的RAD51抑制剂，可特异性抑制RAD51-dsDNA的结合。

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