Department of Radiation Medicine, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Department of Medical Bioinformatics, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Oncogene. 2020 Nov;39(47):7051-7062. doi: 10.1038/s41388-020-01482-x. Epub 2020 Sep 28.
Multiple RNA processing events including transcription, mRNA splicing, and export are delicately coordinated by the TREX complex. As one of the essential subunits, DDX39B couples the splicing and export machineries by recruiting ALYREF onto mRNA. In this study, we further explore the functions of DDX39B in handling damaged DNA, and unexpectedly find that DDX39B facilitates DNA repair by homologous recombination through upregulating BRCA1. Specifically, DDX39B binds to and stabilizes BRCA1 mRNA. DDX39B ensures ssDNA formation and RAD51 accumulation at DSB sites by maintaining BRCA1 levels. Without DDX39B being present, ovarian cancer cells exhibit hypersensitivity to DNA-damaging chemotherapeutic agents like platinum or PARPi. Moreover, DDX39B-deficient mice show embryonic lethality or developmental retardation, highly reminiscent of those lacking BRCA1. High DDX39B expression is correlated with worse survival in ovarian cancer patients. Thus, DDX39B suppression represents a rational approach for enhancing the efficacy of chemotherapy in BRCA1-proficient ovarian cancers.
多个 RNA 加工事件，包括转录、mRNA 剪接和输出，都被 TREX 复合物精细地协调。作为必需亚基之一，DDX39B 通过将 A LYREF 募集到 mRNA 上来连接剪接和输出机制。在这项研究中，我们进一步探索了 DDX39B 在处理受损 DNA 方面的功能，出乎意料地发现 DDX39B 通过上调 BRCA1 促进同源重组修复。具体而言，DDX39B 与 BRCA1 mRNA 结合并稳定其结构。DDX39B 通过维持 BRCA1 水平来确保 DSB 部位形成单链 DNA 和 RAD51 积累。没有 DDX39B 的存在，卵巢癌细胞对铂类或 PARPi 等 DNA 损伤化疗药物表现出高度敏感性。此外，DDX39B 缺陷小鼠表现出胚胎致死或发育迟缓，与缺乏 BRCA1 的情况非常相似。高 DDX39B 表达与卵巢癌患者的生存预后较差相关。因此，抑制 DDX39B 代表了增强 BRCA1 阳性卵巢癌化疗疗效的合理方法。
