Tumor-associated intronic editing of HNRPLL generates a novel splicing variant linked to cell proliferation
Tumor-associated intronic editing of HNRPLL generates a novel splicing variant linked to cell proliferation
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DOI：
10.1074/jbc.ra117.001197
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发表时间：
2018-06-29
影响因子：
4.8
通讯作者：
Tan, Bertrand Chin-Ming
中科院分区：
文献类型：
--
作者：
Chen, Yi-Tung;Chang, Ian Yi-Feng;Tan, Bertrand Chin-Ming
真核生物转录组的加工是一种动态调控机制，赋予遗传多样性，剪接和腺苷到肌苷（a -to- i） RNA编辑是这种加工的典型例子。越来越多的证据揭示了剪接和RNA编辑之间的串扰，但缺乏关于其机制细节和在生理背景下的贡献的实质性证据。在这里，我们的研究结果表明，肿瘤相关的差异RNA编辑与剪接机制一起，调节了编码剪接因子的基因HNRPLL变体的表达。我们发现了一个HNRPLL转录本变体包含一个额外的外显子12A (E12A)，它是ADAR1和ADAR2的底物。腺苷脱氨酶作用于RNA （ADAR）直接脱氨酶依赖于E12A转录物的表达，ADAR介导的E12A调控主要基于剪接，不影响转录物的稳定性或核质分布。此外，adar介导的外显子12A的修饰产生了致癌剪接因子SRSF1的增强子，从而提高了选择性剪接的频率。RNA-seq基因表达谱显示，E12A与HNRPLL的作用不同，并调控一组生长相关基因，如细胞周期蛋白CCND1和生长因子受体TGFBR1。因此，沉默E12A表达导致克隆生成能力受损，对阿霉素的敏感性增强，从而突出了这种替代异构体在肿瘤细胞存活中的重要性。综上所述，我们提出了RNA编辑和剪接作为基因表达的调节机制及其生理相关性的相互作用。这些发现扩展了我们对转录动力学的理解，并为RNA编辑器与肿瘤发生的联系提供了机制解释。
Processing of the eukaryotic transcriptome is a dynamic regulatory mechanism that confers genetic diversity, and splicing and adenosine to inosine (A-to-I) RNA editing are well-characterized examples of such processing. Growing evidence reveals the cross-talk between the splicing and RNA editing, but there is a paucity of substantial evidence for its mechanistic details and contribution in a physiological context. Here, our findings demonstrate that tumor-associated differential RNA editing, in conjunction with splicing machinery, regulates the expression of variants of HNRPLL, a gene encoding splicing factor. We discovered an HNRPLL transcript variant containing an additional exon 12A (E12A), which is a substrate of ADAR1 and ADAR2. Adenosine deaminases acting on RNA (ADAR) direct deaminase-dependent expression of the E12A transcript, and ADAR-mediated regulation of E12A is largely splicing-based, and does not affect the stability or nucleocytoplasmic distribution of the transcript. Furthermore, ADAR-mediated modification of exon 12A generates an enhancer for the oncogenic splicing factor SRSF1 and consequently promotes the frequency of alternative splicing. Gene expression profiling by RNA-seq revealed that E12A acts distinctly from HNRPLL and regulates a set of growth-related genes, such as cyclin CCND1 and growth factor receptor TGFBR1. Accordingly, silencing E12A expression leads to impaired clonogenic ability and enhanced sensitivity to doxorubicin, thus highlighting the significance of this alternative isoform in tumor cell survival. In summary, we present the interplay of RNA editing and splicing as a regulatory mechanism of gene expression and also its physiological relevance. These findings extend our understanding of transcriptional dynamics and provide a mechanistic explanation to the link of RNA editors to tumorigenesis.