Sun Yue, Bao Yufang, Han Wenjian, Song Fan, Shen Xianfeng, Zhao Jiawei, Zuo Ji, Saffen David, Chen Wei, Wang Zefeng, You Xintian, Wang Yongbo
School of Life Sciences, Fudan University, Shanghai 200438, China.
Institutes of Brain Science, Fudan University, Shanghai 200032, China.
Nucleic Acids Res. 2017 Aug 21;45(14):8524-8540. doi: 10.1093/nar/gkx508.
Mutations in the spliceosomal RNA binding protein RBM10 cause TARP syndrome and are frequently observed in lung adenocarcinoma (LUAD). We have previously shown that RBM10 enhances exon skipping of its target genes, including its paralog RBM5. Here, we report that RBM10 negatively regulates its own mRNA and protein expression and that of RBM5 by promoting alternative splicing-coupled nonsense-mediated mRNA decay (AS-NMD). Through computational analysis and experimental validation, we identified RBM10-promoted skipping of exon 6 or 12 in RBM10 and exon 6 or 16 in RBM5 as the underlying AS-NMD events. Importantly, we showed that LUAD-associated mutations affecting splice sites of RBM10 exons 6 or 12 abolished exon inclusion and correlated with reduced expression of RBM10 RNA. Together, our investigations have revealed novel molecular mechanisms underlying RBM10 autoregulation and cross-regulation of RBM5, thereby providing insights concerning the functions of RBM10 under various physiological and pathological conditions. Our combined computational and experimental approach should be useful for elucidating the role of AS-NMD in auto- and cross-regulation by other splicing regulators.
剪接体RNA结合蛋白RBM10的突变会导致TARP综合征，并且在肺腺癌（LUAD）中经常被观察到。我们之前已经表明，RBM10会增强其靶基因（包括其旁系同源基因RBM5）的外显子跳跃。在此，我们报告RBM10通过促进可变剪接偶联的无义介导的mRNA降解（AS-NMD）来负向调节其自身的mRNA和蛋白质表达以及RBM5的表达。通过计算分析和实验验证，我们确定RBM10促进RBM10中第6或12外显子以及RBM5中第6或16外显子的跳跃是潜在的AS-NMD事件。重要的是，我们表明影响RBM10第6或12外显子剪接位点的LUAD相关突变消除了外显子包含，并与RBM10 RNA表达降低相关。总之，我们的研究揭示了RBM10自我调节和RBM5交叉调节的新分子机制，从而为RBM10在各种生理和病理条件下的功能提供了见解。我们结合计算和实验的方法对于阐明AS-NMD在其他剪接调节因子的自我和交叉调节中的作用应该是有用的。
