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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM061518-14
Application #
8773805
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
2000-07-01
Project End
2018-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
14
Fiscal Year
2014
Total Cost
$354,225
Indirect Cost
$114,225
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Roy, Kevin; Gabunilas, Jason; Gillespie, Abigail et al. (2016) Common genomic elements promote transcriptional and DNA replication roadblocks. Genome Res 26:1363-1375
Al-Hadid, Qais; Roy, Kevin; Chanfreau, Guillaume et al. (2016) Methylation of yeast ribosomal protein Rpl3 promotes translational elongation fidelity. RNA 22:489-98
Hodko, Domagoj; Ward, Taylor; Chanfreau, Guillaume (2016) The Rtr1p CTD phosphatase autoregulates its mRNA through a degradation pathway involving the REX exonucleases. RNA 22:559-70
Gabunilas, Jason; Chanfreau, Guillaume (2016) Splicing-Mediated Autoregulation Modulates Rpl22p Expression in Saccharomyces cerevisiae. PLoS Genet 12:e1005999
Chanfreau, Guillaume (2015) Two degrading decades for RNA. RNA 21:584-5
Kawashima, Tadashi; Douglass, Stephen; Gabunilas, Jason et al. (2014) Widespread use of non-productive alternative splice sites in Saccharomyces cerevisiae. PLoS Genet 10:e1004249
Roy, Kevin; Chanfreau, Guillaume (2014) Stress-induced nuclear RNA degradation pathways regulate yeast bromodomain factor 2 to promote cell survival. PLoS Genet 10:e1004661
Al-Hadid, Qais; Roy, Kevin; Munroe, William et al. (2014) Histidine methylation of yeast ribosomal protein Rpl3p is required for proper 60S subunit assembly. Mol Cell Biol 34:2903-16
Hartman, Elon; Wang, Zhonghua; Zhang, Qi et al. (2013) Intrinsic dynamics of an extended hydrophobic core in the S. cerevisiae RNase III dsRBD contributes to recognition of specific RNA binding sites. J Mol Biol 425:546-62
Lee, Yueh-Jung; Lee, Chrissie Young; Grzechnik, Agnieszka et al. (2013) RNA polymerase I stability couples cellular growth to metal availability. Mol Cell 51:105-15

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