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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2021)

During times of unpredictable stress, organisms must adapt their gene expression to maximize survival. Along with changes in transcription, one conserved means of gene regulation during conditions that quickly represses translation is the formation of cytoplasmic phase-separated mRNP (messenger ribonucleoprotein) granules. Two well-known stress-induced mRNP granules are processing bodies (P-bodies) and stress granules. Previously, we identified that distinct steps in gene expression can be coupled during glucose starvation stress as promoter sequences in the nucleus are able to direct the subcellular localization to or excluded from the phase-separated granules and translatability of mRNAs in the cytosol. During my Ph.D., I have been investigating the underlying mechanisms of how promoter dictates the cytoplasmic fate of mRNAs during glucose starvation. Chapter 1 is a background introduction of the questions I asked. In chapter 2, I led a discovery of a promoter-directed mechanism mediated by AAA+ proteins Rvb1/Rvb2 that couple the transcription, mRNA cytoplasmic localization, and translation of select genes during glucose starvation. In chapter 3, colleagues and I reviewed recent findings regarding stress-related phase-separated granules and shared our insights. Chapter 4 describes 3 projects that aimed to answer the promoter-dictation question from other perspectives, such as expression timing and promoter motifs. Finally, Chapter 5 discusses insights and future directions for my thesis work. I anticipate that these studies will provide us with more insights into complex gene regulation during stressful and pathological conditions.

  • 4 supplemental ZIPs
Cover page: Investigating promoter-driven mRNA localization and translational control during stress
  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2019)
In response to stress, cells must quickly reprogram gene expression to adapt and survive. This is achieved in part by altering levels of mRNAs and their translation into proteins. Recently, the formation of two stress-induced messenger ribonucleoprotein (mRNP) assemblies named stress granules and processing bodies has been postulated to directly impact gene expression during stress. These assemblies sequester and concentrate specific proteins and RNAs away from the larger cytoplasm during stress, thereby providing a layer of posttranscriptional gene regulation with the potential to directly impact mRNA levels, protein translation, and cell survival. The function of these granules has generally been ascribed either by the protein components concentrated into them or, more broadly, by global changes that occur during stress. Recent proteome- and transcriptome-wide studies have provided a more complete view of stress-induced mRNP granule composition in varied cell types and stress conditions. However, direct measurements of the phenotypic and functional consequences of stress granule and processing body formation are lacking. This leaves our understanding of their roles during stress incomplete. Continued study into the function of these granules will be an important part in elucidating how cells respond to and survive stressful environmental changes. This article is categorized under: Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Export and Localization > RNA Localization.
    Cover page: Stress‐induced mRNP granules: Form and function of processing bodies and stress granules
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2022)
    During times of unpredictable stress, organisms must adapt their gene expression to maximize survival. Along with changes in transcription, one conserved means of gene regulation during conditions that quickly repress translation is the formation of cytoplasmic phase-separated mRNP granules such as P-bodies and stress granules. Previously, we identified that distinct steps in gene expression can be coupled during glucose starvation as promoter sequences in the nucleus are able to direct the subcellular localization and translatability of mRNAs in the cytosol. Here, we report that Rvb1 and Rvb2, conserved ATPase proteins implicated as protein assembly chaperones and chromatin remodelers, were enriched at the promoters and mRNAs of genes involved in alternative glucose metabolism pathways that we previously found to be transcriptionally upregulated but translationally downregulated during glucose starvation in yeast. Engineered Rvb1/Rvb2-binding on mRNAs was sufficient to sequester mRNAs into mRNP granules and repress their translation. Additionally, this Rvb tethering to the mRNA drove further transcriptional upregulation of the target genes. Further, we found that depletion of Rvb2 caused decreased alternative glucose metabolism gene mRNA induction, but upregulation of protein synthesis during glucose starvation. Overall, our results point to Rvb1/Rvb2 coupling transcription, mRNA granular localization, and translatability of mRNAs during glucose starvation. This Rvb-mediated rapid gene regulation could potentially serve as an efficient recovery plan for cells after stress removal.
      Cover page: Rvb1/Rvb2 proteins couple transcription and translation during glucose starvation
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2020)
      Mitochondria are dynamic organelles that must precisely control their protein composition according to cellular energy demand. Although nuclear-encoded mRNAs can be localized to the mitochondrial surface, the importance of this localization is unclear. As yeast switch to respiratory metabolism, there is an increase in the fraction of the cytoplasm that is mitochondrial. Our data point to this change in mitochondrial volume fraction increasing the localization of certain nuclear-encoded mRNAs to the surface of the mitochondria. We show that mitochondrial mRNA localization is necessary and sufficient to increase protein production to levels required during respiratory growth. Furthermore, we find that ribosome stalling impacts mRNA sensitivity to mitochondrial volume fraction and counterintuitively leads to enhanced protein synthesis by increasing mRNA localization to mitochondria. This points to a mechanism by which cells are able to use translation elongation and the geometric constraints of the cell to fine-tune organelle-specific gene expression through mRNA localization.
        Cover page: Mitochondrial volume fraction and translation duration impact mitochondrial mRNA localization and protein synthesis
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