The Nucleolar Detention Center: a Hub of Long Noncoding RNAs that Imprison Proteins During Stress (Note: papers from our group are cited) PROJECT SUMMARY The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various pathophysiological settings, including development, cancer and neurological disorders. We recently reported the unexpected discovery of stress-induced long noncoding RNAs derived from stimuli-specific loci of the ribosomal intergenic spacer (Mol. Cell (2012) 45:147), an enigmatic region of the human genome assumed to be transcriptionally inactive. Induction of intergenic spacer RNA (IGSRNA) converts the nucleolus from a factory of ribosomes to the nucleolar detention center: a molecular prison that detains specific proteins in response to extracellular stressors (Nature Cell Biol. (2004) 6:642; J.Cell. Biol. (2005) 170:733; Mol. Biol. Cell. (2013) 24: 2943). IGSRNAs capture and immobilize proteins in the nucleolar detention center by interacting with the Nucleolar Detention Sequence (NoDS), a discrete peptide code that regulates protein mobility (Mol. Biol. Cell (2007) 19:3966). We will show preliminary data that the rDNA intergenic spacer produces an array of novel and complex IGSRNAs that confine within the nucleolus distinct groups of proteins, depending upon environment cues. This enables cells to tailor their biological response to various adverse conditions by temporarily arresting critical pathways including DNA replication, transcription, translation and protein degradation. Based on these aforementioned rationales, we propose the following hypothesis: IGSRNAs induce cellular acclimatization to environmental stressors by capturing and immobilizing distinct proteins in the nucleolar detention center. In the Specific Aims, we will: 1- decipher the ribosomal intergenic spacer as a hub of lncRNAs responsive to environmental cues; 2- uncover the stimuli-specific nucleolar detention centers; 3- explore the biological and biochemical consequences of stress-specific IGSRNA-induced nucleolar detention. The discovery of the IGSRNA-regulated nucleolar detention pathway opens a unique and remarkable window of opportunity to investigate a largely unexplored post-translational mechanism involved in the cellular stress response. Study of the IGSRNA-directed pathway will yield significant conceptual advances in our understanding of critical adaptive/resistance processes to stressors encounter by cells, such as the acidotic tumor microenvironment, hyperthermia, and exposure to anti-cancer drugs.

Public Health Relevance

The Nucleolar Detention Center: a Hub of Long Noncoding RNAs that Imprison Proteins during Stress NARRATIVE Our cells encounter various adverse environmental conditions during their life including exposure to toxins, high temperature or lack of oxygen. My group has recently discovered a novel class of RNA molecules that are involved in policing cells under stress. These RNAs function to temporary imprison specific proteins that the cell does not want so it can survive harmful conditions. We want to understand how these new RNAs function so that we can make our normal cells live when they are exposed to damaging incidents including stroke and heart attack or make resistant tumor cells die during cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM115342-01
Application #
8936277
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Reddy, Michael K
Project Start
2015-07-24
Project End
2019-04-30
Budget Start
2015-07-24
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
$303,163
Indirect Cost
$105,663
Name
University of Miami School of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Wang, Miling; Audas, Timothy E; Lee, Stephen (2017) Disentangling a Bad Reputation: Changing Perceptions of Amyloids. Trends Cell Biol 27:465-467
Ho, J J David; Lee, Stephen (2016) A Cap for Every Occasion: Alternative eIF4F Complexes. Trends Biochem Sci 41:821-3
Ho, J J David; Wang, Miling; Audas, Timothy E et al. (2016) Systemic Reprogramming of Translation Efficiencies on Oxygen Stimulus. Cell Rep 14:1293-1300
Audas, Timothy E; Audas, Danielle E; Jacob, Mathieu D et al. (2016) Adaptation to Stressors by Systemic Protein Amyloidogenesis. Dev Cell 39:155-168