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.

外显子连接复合体（EJC）在RNA的生命周期中发挥着关键作用，尤其在神经系统中的相关性尤为显著。本研究探讨了EJC成员中两个同源蛋白，MAGOH和MAGOHB，在脑肿瘤发展中的作用。在14种肿瘤类型中观察到MAGOH/MAGOHB的高表达；与正常组织相比，胶质母细胞瘤（GBM）表现出最大的差异。MAGOH/MAGOHB表达的增加与胶质瘤患者的预后不良相关，而MAGOH/MAGOHB的下调则影响了不同的癌症表型。GBM细胞中MAGOH/MAGOHB表达的降低导致了剪接谱的改变，包括多个外显子的重新剪接和跳过。EJC蛋白的结合谱表明，受到MAGOH/MAGOHB敲低影响的外显子平均积累了更少的复合体，这为它们对MAGOH/MAGOHB敲低敏感的可能机制提供了解释。表现出剪接谱改变的转录本（基因）主要涉及细胞分裂、细胞周期、剪接和翻译。我们提出，在高细胞增殖需求的情况下（如脑发育和GBM生长），高水平的MAGOH/MAGOHB对于保障高需求基因的剪接是必要的，以确保高效的细胞分裂、细胞周期调节和基因表达（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，针对这些同源蛋白成为治疗GBM的潜在策略。