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.
Mutations that cause genetic diseases often result in premature translation termination codons, which in turn mediate the rapid degradation of mRNAs encoded by these genes by Nonsense Mediated Decay. Another class of mutations found to cause genetic diseases result in the production of defective polypeptides that lead to translation stalls. Our studies, which aim to identify the substrates of translation-mediated quality control pathways will shed light on the mechanisms by which quality control mechanisms regulate the expression of genes mutated in the context of a large number of genetic diseases.
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