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.

哺乳动物细胞的核被诸如核斑点之类的核体隔开，但是，尚未积极研究核体特别是核斑点对DNA修复的参与。在这里，我们集中筛选涉及同源重组（HR）的核斑点因子，这是一个忠实的DNA双链断裂（DSB）修复机制，确定了转录相关的核斑点因子是潜在的HR调节剂。在热门文章中，我们提供的证据表明，USP42是迄今尚未鉴定的核斑点蛋白，它通过促进BRCA1募集到DSB位点和DNA末端切除来促进HR。我们进一步表明，USP42本地化到核斑点是有效的HR所必需的。此外，我们确定USP42与具有DNA-RNA解旋酶活性的DHX9相互作用，并且是有效解析DSB诱导的R环所必需的。总之，我们的数据提出了一个模型，其中USP42促进BRCA1加载到DSB位点，解决DSB诱导的R环和HR优先进行DSB修复，表明核斑点介导的DSB修复调控的重要性。