MAGOH 和 MAGOHB 的对映体是高级别胶质瘤的致癌因子,可保护细胞分裂和细胞周期基因的剪接。

IF 3.6 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Rodrigo A S Barreiro, Gabriela D A Guardia, Fabiana M Meliso, Xiufen Lei, Wei-Qing Li, Andre Savio, Martin Fellermeyer, Helena B Conceição, Rafael L V Mercuri, Tesha Landry, Mei Qiao, Lorea Blazquez, Jernej Ule, Luiz O F Penalva, Pedro A F Galante
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引用次数: 0

摘要

外显子连接复合体(EJC)在 RNA 的整个生命周期中发挥着关键作用,尤其是在神经系统中。我们研究了 EJC 的两个成员,即 MAGOH 和 MAGOHB 的旁系亲属在脑肿瘤发展中的作用。在14种肿瘤类型中观察到了MAGOH/MAGOHB的高表达;与正常组织相比,胶质母细胞瘤(GBM)的差异最大。在胶质瘤患者中,MAGOH/MAGOHB表达的增加与预后不良有关,而MAGOH/MAGOHB的敲除会影响不同的癌症表型。MAGOH/MAGOHB在GBM细胞中的表达减少会导致剪接曲线的改变,包括重新剪接和跳过多个外显子。EJC蛋白的结合图谱表明,受MAGOH/MAGOHB基因敲除影响的外显子平均积累的复合物较少,这为它们对MAGOH/MAGOHB基因敲除的敏感性提供了可能的解释。剪接谱发生变化的转录本(基因)主要与细胞分裂、细胞周期、剪接和翻译有关。我们认为,在需要增加细胞增殖(大脑发育和 GBM 生长)的情况下,需要高水平的 MAGOH/MAGOHB 来保护高需求基因的剪接,确保高效的细胞分裂、细胞周期调控和基因表达(剪接和翻译)。由于分化的神经元细胞不需要增加 MAGOH/MAGOHB 的表达,因此靶向这些旁系亲属是治疗 GBM 的一个潜在选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes.

The exon junction complex (EJC) plays key roles throughout the lifespan of RNA and is particularly relevant in the nervous system. We investigated the roles of two EJC members, the paralogs MAGOH and MAGOHB, with respect to brain tumour development. High MAGOH/MAGOHB expression was observed in 14 tumour types; glioblastoma (GBM) showed the greatest difference compared to normal tissue. Increased MAGOH/MAGOHB expression was associated with poor prognosis in glioma patients, while knockdown of MAGOH/MAGOHB affected different cancer phenotypes. Reduced MAGOH/MAGOHB expression in GBM cells caused alterations in the splicing profile, including re-splicing and skipping of multiple exons. The binding profiles of EJC proteins indicated that exons affected by MAGOH/MAGOHB knockdown accumulated fewer complexes on average, providing a possible explanation for their sensitivity to MAGOH/MAGOHB knockdown. Transcripts (genes) showing alterations in the splicing profile are mainly implicated in cell division, cell cycle, splicing, and translation. We propose that high MAGOH/MAGOHB levels are required to safeguard the splicing of genes in high demand in scenarios requiring increased cell proliferation (brain development and GBM growth), ensuring efficient cell division, cell cycle regulation, and gene expression (splicing and translation). Since differentiated neuronal cells do not require increased MAGOH/MAGOHB expression, targeting these paralogs is a potential option for treating GBM.

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来源期刊
RNA Biology
RNA Biology 生物-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
82
审稿时长
1 months
期刊介绍: RNA has played a central role in all cellular processes since the beginning of life: decoding the genome, regulating gene expression, mediating molecular interactions, catalyzing chemical reactions. RNA Biology, as a leading journal in the field, provides a platform for presenting and discussing cutting-edge RNA research. RNA Biology brings together a multidisciplinary community of scientists working in the areas of: Transcription and splicing Post-transcriptional regulation of gene expression Non-coding RNAs RNA localization Translation and catalysis by RNA Structural biology Bioinformatics RNA in disease and therapy
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