The Control of Gene Expression by Eukaryotic Ribonucleases

描述（由申请人提供）：RNA降解提供了通过微调基因的转录输出来调节基因表达的有效方式，而且还提供了消除无功能或异常的RNA分子的机制，用作遗传信息流中的质量控制（QC）机制。翻译偶联的QC途径确保翻译缺陷的RNA，无论是因为存在提前终止密码子，还是因为它们在翻译中停滞，都会被快速降解。这些抑制偶联的QC途径发挥重要作用，不仅因为它们消除了非功能性分子，还因为它们广泛参与基因表达控制。本提案的目标是研究这些质量控制机制控制基因表达的三个主要途径。我们将研究通过无义介导的衰变（NMD）降解的5 '延伸RNA介导其同源基因的转录抑制的机制，并将分析这些5'延伸RNA在全基因组范围内的影响。我们将分析通常由NMD靶向的mRNA通过一类新的不稳定非编码RNA的调节，这些不稳定RNA与它们的3 '-UTR相关，以及这些不稳定RNA促进其mRNA靶稳定的机制。最后，我们将研究No-Go衰变对基因表达的影响，并将分析在最近的遗传筛选中鉴定的三种蛋白质的作用，目的是鉴定参与No-Go衰变的新因素。这些研究将提供关键的见解的机制和影响的抑制偶联RNA质量控制基因调控全基因组。

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.