A global perspective of Exon Junction Complexes in Nonsense-mediated mRNA Decay (NMD)

成功处理的到达细胞质的mrna在其外显子连接处被蛋白质复合物结合，这被称为外显子连接复合物（EJC）。EJCs是分子机器的关键组成部分，它控制着细胞质基因调控的不同模式，包括翻译、RNA定位和通过无义介导的衰变控制RNA稳定性。以前，我们已经确定不同类别的mrna被需要不同EJC辅助因子的替代NMD途径靶向。此外，我们还定义了如何组装EJCs以及如何回收供应不足的辅助因素。基于这些“模型mRNA”的发现，我们现在将在转录组水平上探索mRNA:EJC的相互作用。具体来说，我们将分析(1)结合不同类别mrna的EJC的辅因子组成，(2)EJC在mrna上的分布，以及(3)EJC的组成和分布如何在外部刺激和不同细胞类型下发生变化。因此，该项目将解决控制mRNA稳定性的关键机制之一如何在系统水平上促进基因表达的细胞质调节的基本问题。

Successfully processed mRNAs that reach the cytoplasm are bound by protein complexes at their exon junctions, which are referred to as exon junction complexes (EJC). EJCs are critical components of a molecular machine that controls different modes of cytoplasmic gene regulation including translation, RNA localisation, and control of RNA stability by nonsense mediated decay. Previously, we have established that different classes of mRNAs are targeted by alternative NMD pathways that require different EJC co-factors. Further, we have defined how EJCs are assembled and how the co-factors that are in short supply are recycled. Based on these findings with “model mRNAs”, we will now explore mRNA:EJC interactions at a transcriptomic level. Specifically, we will analyze (1) the co-factor composition of EJCs that bind different classes of mRNAs, (2) the distribution of EJCs on mRNAs and (3) how the composition and the distribution of EJC change upon external stimuli and in different cell types. The project will thus address the fundamental question of how one of the key mechanisms controlling mRNA stability contributes to the cytoplasmic regulation of gene expression on a systemic level.