Gong Juanjuan, Huang Min, Wang Fengli, Ma Xiaolu, Liu Hongmei, Tu Yingfeng, Xing Lingyu, Zhu Xuefei, Zheng Hui, Fang Junjie, Li Xiaoling, Wang Qiaochu, Wang Jiuqiang, Sun Zhongshuai, Wang Xi, Wang Yun, Guo Caixia, Tang Tie-Shan
State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
Nucleic Acids Res. 2017 Dec 15;45(22):12862-12876. doi: 10.1093/nar/gkx1102.
DNA damage response (DDR) is essential for genome stability and human health. Recently, several RNA binding proteins (RBPs), including fused-in-sarcoma (FUS), have been found unexpectedly to modulate this process. The role of FUS in DDR is closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Given that RBM45 is also an ALS-associated RBP, we wondered whether RBM45 plays any function during this process. Here, we report that RBM45 can be recruited to laser microirradiation-induced DNA damage sites in a PAR- and FUS-dependent manner, but in a RNA-independent fashion. Depletion of RBM45 leads to abnormal DDR signaling and decreased efficiency in DNA double-stranded break repair. Interestingly, RBM45 is found to compete with histone deacetylase 1 (HDAC1) for binding to FUS, thereby regulating the recruitment of HDAC1 to DNA damage sites. A common familial ALS-associated FUS mutation (FUS-R521C) is revealed to prefer to cooperate with RBM45 than HDAC1. Our findings suggest that RBM45 is a key regulator in FUS-related DDR signaling whose dysfunction may contribute to the pathogenesis of ALS.
DNA损伤反应（DDR）对于基因组稳定性和人类健康至关重要。最近，人们意外地发现包括融合肉瘤蛋白（FUS）在内的几种RNA结合蛋白（RBPs）可调节这一过程。FUS在DDR中的作用与肌萎缩侧索硬化症（ALS）的发病机制密切相关，ALS是一种影响大脑和脊髓神经细胞的进行性神经退行性疾病。鉴于RBM45也是一种与ALS相关的RBP，我们想知道RBM45在此过程中是否发挥任何作用。在此，我们报告RBM45可以以PAR和FUS依赖的方式，但以RNA非依赖的方式被募集到激光微照射诱导的DNA损伤位点。RBM45的缺失会导致DDR信号异常以及DNA双链断裂修复效率降低。有趣的是，发现RBM45与组蛋白脱乙酰基酶1（HDAC1）竞争与FUS结合，从而调节HDAC1向DNA损伤位点的募集。一种常见的与家族性ALS相关的FUS突变（FUS-R521C）显示比HDAC1更倾向于与RBM45合作。我们的研究结果表明，RBM45是FUS相关DDR信号传导中的关键调节因子，其功能障碍可能导致ALS的发病机制。
