Solid-Phase Separation of Toxic Phosphorothioate Antisense Oligonucleotide-Protein Nucleolar Aggregates Is Cytoprotective.

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  • Additional Information
    • Source:
      Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101562758 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-3345 (Electronic) Linking ISSN: 21593337 NLM ISO Abbreviation: Nucleic Acid Ther Subsets: MEDLINE
    • Publication Information:
      Original Publication: New Rochelle, N.Y. : Mary Ann Liebert, Inc.
    • Subject Terms:
      Cytoprotection/*drug effects ; Oligonucleotides, Antisense/*pharmacology ; Phosphorothioate Oligonucleotides/*pharmacology; Cell Nucleus/drug effects ; Cell Proliferation/drug effects ; HeLa Cells ; Humans ; Oligonucleotides, Antisense/chemistry ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/isolation & purification ; Phosphorothioate Oligonucleotides/chemistry ; Phosphorothioate Oligonucleotides/genetics ; Phosphorothioate Oligonucleotides/isolation & purification ; Protein Aggregates/genetics ; Protein Binding/drug effects ; Ribonucleoproteins/chemistry ; Ribonucleoproteins/genetics
    • Abstract:
      Phosphorothioate antisense oligonucleotides (PS-ASOs) interact with proteins and can localize to or induce the formation of a variety of subcellular PS-ASO-protein or PS-ASO-ribonucleoprotein aggregates. In this study, we show that these different aggregates that form with varying compositions at various concentrations in the cytosol, nucleus, and nucleolus may undergo phase separations in cells. Some aggregates can form with both nontoxic and toxic PS-ASOs, such as PS bodies, paraspeckles, and nuclear filaments. However, toxic PS-ASOs have been shown to form unique nucleolar aggregates that result in nucleolar dysfunction and apoptosis. These include liquid-like aggregates that we labeled "cloudy nucleoli" and solid-like perinucleolar filaments. Toxic nucleolar aggregates may undergo solid-phase separation and in the solid phase, protein mobility in and out of the aggregates is limited. Other aggregates appear to undergo liquid-phase separation, including paraspeckles and perinucleolar caps, in which protein mobility is negatively correlated with the binding affinity of the proteins to PS-ASOs. However, PS bodies and nuclear filaments are solid-like aggregates. Importantly, in cells that survived treatment with toxic PS-ASOs, solid-like PS-ASO aggregates accumulated, especially Hsc70-containing nucleolus-like structures, in which modest pre-rRNA transcriptional activity was retained and appeared to mitigate the nucleolar toxicity. This is the first demonstration that exogenous drugs, PS-ASOs, can form aggregates that undergo phase separations and that solid-phase separation of toxic PS-ASO-induced nucleolar aggregates is cytoprotective.
    • Contributed Indexing:
      Keywords: PS-ASO; filaments; nucleolus; paraspeckle; phase separation; protein
    • Accession Number:
      0 (Oligonucleotides, Antisense)
      0 (Phosphorothioate Oligonucleotides)
      0 (Protein Aggregates)
      0 (Ribonucleoproteins)
    • Publication Date:
      Date Created: 20210203 Date Completed: 20211122 Latest Revision: 20211122
    • Publication Date:
      20240105
    • Accession Number:
      10.1089/nat.2020.0923
    • Accession Number:
      33534636