USP42 enhances homologous recombination repair by promoting R-loop resolution with a DNA-RNA helicase DHX9
USP42 enhances homologous recombination repair by promoting R-loop resolution with a DNA-RNA helicase DHX9
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DOI：
10.1038/s41389-020-00244-4
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发表时间：
2020-06-15
期刊：
影响因子：
6.2
通讯作者：
Nishi, Ryotaro
中科院分区：
文献类型：
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作者：
Matsui, Misaki;Sakasai, Ryo;Nishi, Ryotaro
哺乳动物细胞核是由核小体（如核斑点）划分的，然而，核小体，特别是核斑点在DNA修复中的作用尚未得到积极的研究。在这里，我们重点筛选了参与同源重组（HR）的核散斑因子，这是一种忠实的DNA双链断裂（DSB）修复机制，确定了转录相关的核散斑因子作为潜在的HR调节因子。在最热门的发现中，我们提供的证据表明，USP42是一种迄今尚未发现的核斑点蛋白，通过促进BRCA1招募到DSB位点和dna末端切除来促进HR。我们进一步表明，USP42定位到核斑点是有效HR的必要条件。此外，我们确定USP42与DHX9相互作用，DHX9具有DNA-RNA解旋酶活性，是有效分解dsb诱导的R-loop所必需的。总之，我们的数据提出了一个USP42促进BRCA1加载到DSB位点，分解DSB诱导的r环和HR优先修复DSB的模型，这表明核斑点介导的DSB修复调节的重要性。
The nucleus of mammalian cells is compartmentalized by nuclear bodies such as nuclear speckles, however, involvement of nuclear bodies, especially nuclear speckles, in DNA repair has not been actively investigated. Here, our focused screen for nuclear speckle factors involved in homologous recombination (HR), which is a faithful DNA double-strand break (DSB) repair mechanism, identified transcription-related nuclear speckle factors as potential HR regulators. Among the top hits, we provide evidence showing that USP42, which is a hitherto unidentified nuclear speckles protein, promotes HR by facilitating BRCA1 recruitment to DSB sites and DNA-end resection. We further showed that USP42 localization to nuclear speckles is required for efficient HR. Furthermore, we established that USP42 interacts with DHX9, which possesses DNA-RNA helicase activity, and is required for efficient resolution of DSB-induced R-loop. In conclusion, our data propose a model in which USP42 facilitates BRCA1 loading to DSB sites, resolution of DSB-induced R-loop and preferential DSB repair by HR, indicating the importance of nuclear speckle-mediated regulation of DSB repair.