Deciphering human nonsense-mediated mRNA decay (NMD)

破译人类无义介导的 mRNA 衰变 (NMD)

• 批准号: 313641849
• 负责人: Professor Dr. Christoph Dieterich
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/313641849?language=en
• 关键词: Deciphering; human; nonsense; mediated; mRNA

In eukaryotic cells several quality control mechanisms help to detect defective or irregular mRNAs and to avoid the production of incorrect polypeptides. A well-studied degradation pathway, referred to as nonsense mediated mRNA decay (NMD), degrades transcripts containing premature translation termination codons (PTC). NMD exists in all eukaryotic organisms and employs a conserved set of core factors to eliminate aberrant transcripts that fail to terminate translation at a proper position. The activity of NMD is not restricted to mRNAs carrying disease-causing nonsense mutations. In fact, the majority of NMD substrates is produced by alternative mRNA processing, resulting in the inclusion of PTCs into the mature transcript. Hence, NMD functions as a general modulator of gene expression and directly or indirectly alters the expression levels of about 5% of the transcriptome in eukaryotic cells. Despite the importance of NMD for the composition of the transcriptome, only a small number of transcripts that activate NMD by alternative processing have been studied in detail. In order to close this knowledge gap, we will use state-of-the-art methods to manipulate the NMD machinery, which will allow us to compile a catalogue of all NMD-activating transcript isoforms in human cells. Using this new set of NMD targets we will address important mechanistic questions regarding the early commitment phase as well as the degradation phase of NMD. We will also produce computational methods to systematically test the effect of NMD on post-transcriptional regulation of gene expression.

在真核细胞中，几种质量控制机制有助于检测有缺陷或不规则的mRNA，并避免产生不正确的多肽。一个被充分研究的降解途径，称为无义介导的mRNA衰变（NMD），降解含有提前翻译终止密码子（PTC）的转录本。NMD存在于所有真核生物中，并利用一组保守的核心因子来消除未能在适当位置终止翻译的异常转录物。NMD的活性不限于携带致病无义突变的mRNA。事实上，大多数NMD底物是通过替代mRNA加工产生的，导致PTC被包含到成熟转录物中。因此，NMD作为基因表达的一般调节剂起作用，并直接或间接改变真核细胞中约5%的转录组的表达水平。尽管NMD的转录组的组成的重要性，只有少量的转录激活NMD的替代加工已被详细研究。为了缩小这一知识差距，我们将使用最先进的方法来操纵NMD机制，这将使我们能够汇编人类细胞中所有NMD激活转录本亚型的目录。利用这套新的NMD目标，我们将解决有关NMD的早期承诺阶段以及降级阶段的重要机制问题。我们还将产生计算方法来系统地测试NMD对基因表达的转录后调控的影响。