title: Altered stoichiometry and nuclear delocalization of NonO and PSF promote cellular senescence.
abstract: While cellular senescence is a critical mechanism to prevent malignant transformation of potentially mutated cells, persistence of senescent cells can also promote cancer and aging phenotypes. NonO/p54nrb and PSF are multifunctional hnRNPs typically found as a complex exclusively within the nuclei of all mammalian cells. We demonstrate here that either increase or reduction of expression of either factor results in cellular senescence. Coincident with this, we observe expulsion of NonO and PSF-containing nuclear paraspeckles and posttranslational modification at G2/M. That senescence is mediated most robustly by overexpression of a cytoplasmic C-truncated form of NonO further indicated that translocation of NonO and PSF from the nucleus is critical to senescence induction. Modulation of NonO and PSF expression just prior to or coincident with senescence induction disrupts the normally heterodimeric NonO-PSF nuclear complex resulting in a dramatic shift in stoichiometry to heterotetramers and monomer with highest accumulation within the cytoplasm. This is accompanied by prototypic cell cycle checkpoint activation and chromatin condensation. These observations identify yet another role for these multifunctional factors and provide a hitherto unprecedented mechanism for cellular senescence and nuclear-cytoplasmic trafficking.
authors.affiliation: University of Texas at Austin, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, Austin, TX 78712, USA.
authors.forename: Ching-Jung
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: University of Texas at Austin, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, Austin, TX 78712, USA.
authors.forename: Utsab
authors.initials: U
authors.lastname: Das
authors.affiliation: University of Texas at Austin, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, Austin, TX 78712, USA.
authors.forename: Weijun
authors.initials: W
authors.lastname: Xie
authors.affiliation: University of Texas at Austin, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, Austin, TX 78712, USA.
authors.forename: Miryam
authors.initials: M
authors.lastname: Ducasse
authors.affiliation: University of Texas at Austin, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, Austin, TX 78712, USA.
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
mesh_terms: D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D003593:Cytoplasm / Q000502:physiology; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006801:Humans; D008938:Mitosis; D009154:Mutation; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D050810:Octamer Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000072670:PTB-Associated Splicing Factor / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D011499:Protein Processing, Post-Translational; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059506:Telomere Shortening; D014170:Transformation, Genetic; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C083214:NONO protein, human; D034521:Nuclear Matrix-Associated Proteins; D050810:Octamer Transcription Factors; D000072670:PTB-Associated Splicing Factor; D016601:RNA-Binding Proteins
keywords: cancer; cellular senescence; multifunctional proteins; stoichiometry