The Control of Gene Expression by Eukaryotic Ribonucleases

描述(申请人提供)：RNA降解提供了一种通过微调基因转录输出来调节基因表达的有效方法，但也提供了一种消除无功能或异常的RNA分子的机制，作为遗传信息流中的质量控制(QC)机制。翻译耦合的QC途径确保了由于过早终止密码子的存在或因为它们在翻译中停滞不前而缺乏翻译能力的RNA迅速降解。这些翻译偶联的QC途径发挥着重要的作用，不仅因为它们消除了非功能分子，还因为它们广泛地参与了基因表达调控。这项建议的目标是调查这些质量控制机制控制基因表达的三个主要途径。我们将研究5‘-延伸RNA通过无意义介导的衰变(NMD)介导其同源基因转录抑制的降解机制，并分析这些5’-延伸RNA对全基因组的影响。我们将分析一类与其3‘-UTR相关的不稳定非编码RNA对通常被NMD靶向的mRNAs的调节，以及这些不稳定RNAs促进其mRNA靶向稳定的机制。最后，我们将研究No-Go衰变对基因表达的影响，并将分析最近一项旨在确定参与No-Go衰变的新因素的遗传筛查中发现的三种蛋白质的作用。这些研究将为翻译偶联RNA质量控制在基因组范围内对基因调控的机制和影响提供关键的见解。

DESCRIPTION (provided by applicant): RNA degradation provides a potent way to regulate gene expression by fine-tuning the transcriptional output of genes, but also provides a mechanism to eliminate RNA molecules that are non-functional or aberrant, serving as a quality control (QC) mechanism in the flow of the genetic information. Translation-coupled QC pathways ensure that RNAs that are deficient for translation, either because of the presence of premature termination codons, or because they are stalled in translation are quickly degraded. These translation-coupled QC pathways play important roles, not only because they eliminate non-functional molecules, but also because they broadly participate in gene expression control. The goal of this proposal is to investigate three major pathways by which these quality control mechanisms control gene expression. We will investigate the mechanism by which 5'-extended RNAs degraded by nonsense- mediated decay (NMD) mediate transcriptional repression of their cognate genes, and will analyze the impact of these 5'-extended RNAs genome-wide. We will analyze the regulation of mRNAs normally targeted by NMD by a novel class of unstable non-coding RNAs that associate with their 3'-UTR and the mechanisms by which these unstable RNAs promote the stabilization of their mRNA targets. Finally we will investigate the impact of No-Go decay on gene expression and will analyze the role of three proteins identified in a recent genetic screen aimed at identifying novel factors involved in No-Go decay. These studies will provide key insights into the mechanisms and impact of translation-coupled RNA quality control on gene regulation genome-wide.